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Cited by 301Cannabis and Cannabinoid ResearchPain Mechanisms and TreatmentsPain Management and Opioid Use

The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain

Open access
Donvito, Giulia, Nass, Sara R, Wilkerson, Jenny L, Curry, Zachary A, Schurman, Lesley D, Kinsey, Steven G, Lichtman, Aron H·2018·Neuropsychopharmacology
DOI 10.1038/npp.2017.204PMC PMC5719110
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Abstract

A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury. Given that the endogenous cannabinoid (that is, endocannabinoid) system modulates neuronal and immune cell function, both of which play key roles in pain, therapeutics targeting this system hold promise as novel analgesics. Potential therapeutic targets include the cannabinoid receptors, type 1 and 2, as well as biosynthetic and catabolic enzymes of the endocannabinoids N-arachidonoylethanolamine and 2-arachidonoylglycerol. Notably, cannabinoid receptor agonists as well as inhibitors of endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase produce reliable antinociceptive effects, and offer opioid-sparing antinociceptive effects in myriad preclinical inflammatory and neuropathic pain models. Emerging clinical studies show that 'medicinal' cannabis or cannabinoid-based medications relieve pain in human diseases such as cancer, multiple sclerosis, and fibromyalgia. However, clinical data have yet to demonstrate the analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes. Likewise, the question of whether pharmacotherapies aimed at the endocannabinoid system promote opioid-sparing effects in the treatment of pain reflects an important area of research. Here we examine the preclinical and clinical evidence of various endocannabinoid system targets as potential therapeutic strategies for inflammatory and neuropathic pain conditions.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes preclinical and clinical evidence that targeting the endogenous cannabinoid system—CB1/CB2 receptors, FAAH, MAGL, and related enzymes—can reduce inflammatory and neuropathic pain, with strong preclinical antinociceptive and opioid-sparing effects. Clinical cannabinoid medicines show analgesic efficacy in several pain states, but clinical evidence for endocannabinoid-enzyme inhibitors remains essentially limited to one failed FAAH inhibitor trial in knee osteoarthritis.

Key findings

  • Cannabinoid receptor agonists and inhibitors of endocannabinoid-regulating enzymes FAAH and MAGL produce reliable antinociceptive effects across preclinical inflammatory and neuropathic pain models, and offer opioid-sparing effects; a meta-analysis cited by the review found strong preclinical opioid-sparing evidence but only a single study of nine clinical studies provided evidence of opioid-sparing effects in humans.
  • In the CCI nerve-injury model, within three days of surgery 89% of Aβ, 87% of Aδ, and 32% of C fibers are lost, progressing to loss of 94% of myelinated fibers and 73% of unmyelinated fibers within 14 days; FAAH inhibitors produce antinociception without tolerance upon repeated administration, whereas repeated high-dose MAGL inhibitor JZL184 leads to tolerance, though low-dose JZL184 retains effects.
  • Clinical studies show medicinal cannabis or cannabinoid-based medications relieve pain in diseases such as cancer, multiple sclerosis, and fibromyalgia; however, clinical data have yet to demonstrate analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes, and the FAAH inhibitor PF-04457845 failed to relieve knee osteoarthritis pain versus placebo.
  • Chemotherapy-induced peripheral neuropathy affects up to 70% of patients receiving chemotherapy; in a pilot chemotherapy-induced neuropathic pain trial, no statistically significant difference in pain scores was found for oromucosal treatment versus placebo, although five of 16 participants reported a 2-point reduction in pain score.

Methods

  • Narrative review of preclinical and clinical evidence on endocannabinoid system targets for inflammatory and neuropathic pain, covering rodent models such as carrageenan, LPS, CFA, CIA, MIA, CCI, SNL, pSNL, STZ-induced diabetes, chemotherapy-induced neuropathy, and migraine, plus human clinical trials.
  • No primary experiments, systematic search strategy, or quantitative synthesis are described; evidence is organized narratively and in selected overview tables.

Limitations

  • Stated: preclinical inflammatory pain models often administer treatments before inflammation induction and subchronically, and acute manipulation of the endocannabinoid system typically reduces pain measures via CB1 receptors; these experimental limitations must be considered when translating to the clinic.
  • Stated: lack of highly selective CB2 receptor antibodies limits interpretation of some studies; clinical data on endocannabinoid-regulating enzyme inhibitors are limited to a single published report, and adverse events with the FAAH inhibitor BIA-102474-101 involved off-target effects; additional research is needed on standard formulations/dosages and larger subject numbers.
  • Evident: as a narrative review, it does not report systematic inclusion criteria, search methods, or risk-of-bias assessment, and its tables are described as selected/overview rather than exhaustive.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/npp.2017.204

Cites

Statistics

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Claims the paper makes

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  • Interpretationnone given

    Medicinal cannabis or cannabinoid-based medications relieve pain in human diseases such as cancer, multiple sclerosis, and fibromyalgia.

    “Emerging clinical studies show that 'medicinal' cannabis or cannabinoid-based medications relieve pain in human diseases such as cancer, multiple sclerosis, and fibromyalgia.”
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  • Premisecitation

    In the rhesus monkey warm water tail withdrawal paradigm, AEA, THC, and WIN55,212-2 produce dose-dependent antinociceptive effects.

    “In the rhesus monkey warm water tail withdrawal paradigm, the endogenous cannabinoid arachidonoylethanolamine (anandamide; AEA), the primary active constituent of cannabis Δ 9 -tetrahydrocannabinol (THC), and the high efficacy synthetic cannabinoid receptor agonist WIN55,212-2 produce dose-dependent antinociceptive effects (Manning et al, 2001;Vivian et al, 1998).”
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  • Interpretationnone given

    Cannabinoid receptor agonists and inhibitors of the endocannabinoid-regulating enzymes FAAH and MAGL produce reliable antinociceptive effects in preclinical inflammatory and neuropathic pain models.

    “Notably, cannabinoid receptor agonists as well as inhibitors of endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase produce reliable antinociceptive effects, and offer opioid-sparing antinociceptive effects in myriad preclinical inflammatory and neuropathic pain models.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Several clinical studies have demonstrated analgesic effects of cannabinoids in human disease states, including pain associated with diabetes, chemotherapy, multiple sclerosis, and fibromyalgia.

    “Several clinical studies have demonstrated the analgesic effects of cannabinoids in human disease states, including pain associated with diabetes, chemotherapy, multiple sclerosis, and fibromyalgia (Lynch and Ware, 2015;Whiting et al, 2015).”
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    Clinical data have not yet demonstrated the analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes.

    “However, clinical data have yet to demonstrate the analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes.”
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    Premisecitation

    THC and CP55,940 evoke antinociceptive effects in rhesus monkeys.

    “Other studies also demonstrate that THC and another high efficacy cannabinoid receptor agonist, CP55,940, evoke antinociceptive effects in rhesus monkeys (Li et al, 2008;Maguire andFrance, 2014, 2016).”
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    • cites Maguire andFrance, 2014, 2016

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    Interpretationnone given

    Cannabinoid receptor agonists and inhibitors of FAAH and MAGL offer opioid-sparing antinociceptive effects in preclinical inflammatory and neuropathic pain models.

    “Notably, cannabinoid receptor agonists as well as inhibitors of endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase produce reliable antinociceptive effects, and offer opioid-sparing antinociceptive effects in myriad preclinical inflammatory and neuropathic pain models.”
    Quote in the paperSubstantial claim

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    Premisecitation

    MAGL is the primary hydrolytic enzyme for 2-AG and a rate-limiting enzyme in the production of free arachidonic acid in brain, liver, and lung, but not in the gastrointestinal tract or other organs.

    “In addition to being the primary hydrolytic enzyme for 2-AG (Dinh et al, 2002), MAGL is a rate-limiting enzyme in the production of free arachidonic acid in brain, liver, and lung, but not in the gastrointestinal tract or other organs (Nomura et al, 2011).”
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    Interpretationreasoning

    MAGL inhibitors can produce antinociceptive and anti-inflammatory actions through increased levels of 2-AG stimulating cannabinoid receptors, and decreased levels of arachidonic acid and its pro-inflammatory metabolites.

    “Thus, MAGL inhibitors can produce antinociceptive and anti-inflammatory actions through increased levels of 2-AG-stimulating cannabinoid receptors, and decreased levels of arachidonic acid and its pro-inflammatory metabolites.”
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    FAAH hydrolyzes PEA, which does not bind cannabinoid receptors but functions as an endogenous ligand for PPAR-α.

    “Besides serving as the major catabolic enzyme of AEA, FAAH hydrolyzes other bioactive lipids, such as N-palmitoylethanolamine (PEA) (Fezza et al, 2008), which does not bind cannabinoid receptors, but functions as an endogenous ligand for peroxisome proliferator receptor-α (PPAR-α) (Lo Verme et al, 2005).”
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    Interpretationreasoning

    Endogenous cannabinoids inhibit the production of proinflammatory cytokines and increase the production of anti-inflammatory cytokines throughout the inflammatory response.

    “These results suggest that endogenous cannabinoids inhibit the production of proinflammatory cytokines and increase the production of anti-inflammatory cytokines throughout the inflammatory response.”
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    THC and AEA suppress proinflammatory cytokines and enhance anti-inflammatory cytokines in both innate and adaptive immune responses.

    “For example, THC and AEA suppress proinflammatory cytokines and enhance anti-inflammatory cytokines in both innate and adaptive immune responses (Cabral and Griffin-Thomas, 2009).”
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    Selective antagonists of both the CB2 receptor, SR144528, and CB1 receptor, rimonabant, reverse the suppression of IFN-γ and IL-12, indicating that these receptors play necessary roles in the modulation of proinflammatory cytokines.

    “Selective antagonists of both the CB 2 receptor, SR144528, and CB 1 receptor, rimonabant, reverses the suppression of IFN-γ and IL-12, indicating that these receptors play necessary roles in the modulation of proinflammatory cytokines (Klein et al, 1985).”
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    The endocannabinoid system modulates inflammation by shifting the balance of CD4+ Helper T cells through suppression of Th1 proinflammatory activity and promotion of Th2 anti-inflammatory activity.

    “The endocannabinoid system also modulates inflammation by shifting the balance of CD4 + 'Helper' T cells through suppression of Th1 proinflammatory activity and promotion of Th2 anti-inflammatory activity (Yuan et al, 2002).”
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    AEA and 2-AG are present in the synovial fluid of patients affected by both rheumatoid arthritis and osteoarthritis, but not in healthy controls, suggesting an upregulation in response to inflammation and cartilage degradation.

    “Interestingly, AEA and 2-AG are present in the synovial fluid of patients affected by both rheumatoid arthritis and osteoarthritis, but not in healthy controls, suggesting an upregulation in response to inflammation and cartilage degradation (Richardson et al, 2008).”
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    THC inhibits the proliferation of mouse splenic T cells stimulated by concanavalin A, and B cells stimulated by LPS.

    “Similarly, THC inhibits the proliferation of mouse splenic T cells stimulated by concanavalin A, and B cells stimulated by LPS (Klein et al, 1985).”
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    Both CB1 and CB2 receptors are expressed on chondrocytes and within the joint cartilage and subchondral bone of patients with osteoarthritis.

    “Both receptors are expressed on chondrocytes and within the joint cartilage and subchondral bone of patients with osteoarthritis (Dunn et al, 2014(Dunn et al, , 2016)).”
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    In arthritic synovial tissue, fibroblast-like synoviocytes release matrix metalloproteinases that degrade the cartilage extracellular matrix and pro-inflammatory cytokines.

    “In arthritic synovial tissue, FLSs release matrix metalloproteinases that degrade the cartilage extracellular matrix and pro-inflammatory cytokines (Karouzakis et al, 2006).”
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    AEA's attenuation of IL-6 and IL-8 is blocked by the TRPA1 antagonist A967079, but not by CB1 or CB2 receptor antagonists.

    “AEA's attenuation of IL-6 and IL-8 is blocked by the TRPA1 antagonist A967079, but not by CB 1 or CB 2 receptor antagonists (Lowin et al, 2015), indicating that cannabinoids modulate inflammation through multiple pathways.”
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    In rheumatoid arthritis fibroblast-like synoviocytes stimulated by TNFα, AEA attenuates the phosphorylation of p38 and ERK1/2, but not cJUN, indicating a decrease in mitogen-activated protein kinase activation.

    “In rheumatoid arthritis FLSs stimulated by TNFα, AEA attenuates the phosphorylation of p38 and ERK1/2, but not cJUN, indicating a decrease in mitogen-activated protein kinase activation (Lowin et al, 2015).”
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    WIN-55,212-2 inhibits the production of PGE2, expression of iNOS, and the activation of nuclear factor kappa B in bovine chondrocytes.

    “WIN-55,212-2 also inhibits the production of PGE 2 , expression of iNOS, and the activation of nuclear factor kappa B in bovine chondrocytes (Mbvundula et al, 2006).”
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    The selective CB2 receptor agonists GW405833 and JWH133 attenuate edema and restore weight bearing in rat paws injected with carrageenan.

    “The selective CB 2 receptor agonists GW405833 and JWH133 attenuate edema and restore weight bearing in rat paws injected with carrageenan (Clayton et al, 2002;Elmes et al, 2005).”
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    The attenuation of metalloprotease with thrombospondin motifs-4 production is reversed by the selective CB2 receptor antagonist JTE907, but not the selective CB1 receptor antagonist MJ15, indicating that CB2 plays a necessary role in this effect.

    “The attenuation of the metalloprotease with thrombospondin motifs-4 production is reversed by the selective CB 2 receptor antagonist, JTE907, but not the selective CB 1 receptor antagonist, MJ15 indicating that CB 2 plays a necessary role in this effect.”
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    When administered alone, ZCZ011 attenuates carrageenan-induced mechanical allodynia, but does not elicit anti-edematous effects, mediated by CB2 receptors.

    “When administered alone, ZCZ011 attenuates carrageenan-induced mechanical allodynia, but does not elicit anti-edematous effects, mediated by CB 2 receptors.”
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    ZCZ011 does not elicit psychomimetic effects in tetrad assay or substitute for cannabinoids in the drug discrimination paradigm, suggesting that this compound has a reduced side effect profile compared with orthosteric CB1 receptor agonists.

    “The observations that ZCZ011 does not elicit psychomimetic effects in tetrad assay or substitute for cannabinoids in the drug discrimination paradigm, suggesting that this compound has a reduced side effect profile compared with orthosteric CB 1 receptor agonists (Ignatowska-Jankowska et al, 2015b).”
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    Pharmacological inhibition or genetic deletion of FAAH attenuates carrageenan-induced inflammation as well as mechanical allodynia and thermal hyperalgesia.

    “For example, pharmacological inhibition or genetic deletion of FAAH attenuates carrageenan-induced inflammation as well as mechanical allodynia and thermal hyperalgesia (increased sensitivity to a noxious heat stimuli) (Ghosh et al, 2013;Karbarz et al, 2009;Lichtman et al, 2004).”
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    The CB2 receptor agonist O-3223 attenuates hyperalgesia and edema induced by intraplantar injection of LPS, and was reversed by the CB2 receptor antagonist SR144528, but not by rimonabant.

    “The CB 2 receptor agonist O-3223 attenuates hyperalgesia and edema induced by intraplantar injection of LPS, and was reversed by the CB 2 receptor antagonist, SR144528, but not by rimonabant (Kinsey et al, 2011a).”
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    Interpretationcitation

    In general, inhibition of FAAH or MAGL attenuates acute inflammatory pain with reduced cannabimimetic side effects compared with direct-acting CB1 receptor agonists.

    “In general, inhibition of FAAH or MAGL attenuates acute inflammatory pain with reduced cannabimimetic side effects compared with direct-acting CB 1 receptor agonists.”
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    Premisecitation

    FAAH inhibitors attenuate carrageenan-induced edema, an effect that is mediated through the CB2 receptor.

    “FAAH inhibitors also attenuate carrageenaninduced edema, an effect that is mediated through the CB 2 receptor (Holt et al, 2005;Lichtman et al, 2004).”
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    The FAAH inhibitor URB597, or genetic deletion of FAAH, attenuates LPS-induced hyperalgesia and edema.

    “The FAAH inhibitor URB597, or genetic deletion of FAAH, also attenuates LPS-induced hyperalgesia and edema (Naidu et al, 2010).”
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    The anti-hyperalgesic effect of FAAH inhibition in the LPS model was reversed by CB1 receptor antagonism, whereas the anti-edematous effect was reversed by CB2 antagonism.

    “The anti-hyperalgesic effect of FAAH inhibition in the LPS model was reversed by CB 1 receptor antagonism, whereas the anti-edematous effect was reversed by CB 2 antagonism (Naidu et al, 2010).”
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    The selective MAGL inhibitors JZL184 and KML129 attenuate carrageenan-induced mechanical allodynia through CB1 and CB2 receptor-dependent mechanisms, but only CB2 receptors mediate the anti-edematous effects of these inhibitors.

    “The selective MAGL inhibitors JZL184 and KML129 attenuate carrageenan-induced mechanical allodynia through CB 1 and CB 2 receptor-dependent mechanisms, but only CB 2 receptors mediate the antiedematous effects of these inhibitors (Ghosh et al, 2013;Ignatowska-Jankowska et al, 2014).”
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    The anti-allodynic effects of combined FAAH/MAGL inhibition are reversed by either CB1 or CB2 receptor antagonists, whereas only a CB2 receptor antagonist reverses the anti-edematous effects of dual FAAH/MAGL inhibition.

    “The anti-allodynic effects of combined FAAH/MAGL inhibition are reversed by either CB 1 or CB 2 receptor antagonists, whereas only a CB 2 receptor antagonist reverses the anti-edematous effects of dual FAAH/MAGL inhibition.”
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    The anti-allodynic effect of PF-3845 and diclofenac is blocked by SR144528 or rimonabant, indicating that both cannabinoid receptors mediate this antinociceptive effect.

    “The anti-allodynic effect is blocked by SR144528 or rimonabant, indicating that both cannabinoid receptors mediate this antinociceptive effect (Grim et al, 2014).”
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    FABP inhibitors SBFI26 and SBFI50 attenuate carrageenan-induced acute paw edema and thermal hyperalgesia.

    “The FABP inhibitors SBFI26 and SBFI50 attenuate carrageenan-induced acute paw edema and thermal hyperalgesia (Kaczocha et al, 2014).”
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    Localized administration of low dose (2.5 μg) LPS evokes tactile allodynia that is attenuated by FAAH inhibition without inducing paw edema.

    “Localized administration of low dose (ie, 2.5 μg) LPS evokes tactile allodynia that is attenuated by FAAH inhibition without inducing paw edema (Booker et al, 2012).”
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    Genetic deletion of FAAH reduces mechanical allodynia induced by low-dose LPS, but this anti-allodynia is absent in mice expressing FAAH only in nervous tissue and is mediated by both CB1 and CB2 receptors.

    “Genetic deletion of FAAH also reduces mechanical allodynia induced by low-dose LPS, but this anti-allodynia is absent in mice expressing FAAH only in nervous tissue (Booker et al, 2012) and is mediated by both CB 1 and CB 2 receptors.”
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    DAGL-β is highly expressed in macrophages, and its blockade leads to reduced levels of 2-AG, arachidonic acid, and a variety of proinflammatory arachidonic acid metabolites and proinflammatory cytokines in these cells.

    “Specifically, DAGL-β is highly expressed in macrophages, and its blockade leads to reduced levels of 2-AG, arachidonic acid, and a variety of proinflammatory arachidonic acid metabolites and proinflammatory cytokines in these cells (Hsu et al, 2012).”
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    Interpretationreasoning

    Increasing 2-AG levels via MAGL inhibition reduces LPS-induced nociception through a cannabinoid receptor mechanism of action, while decreasing 2-AG levels in peripheral tissue by inhibiting DAGL-β reduces LPS-induced nociception by dampening the innate immune response.

    “Thus, increasing 2-AG levels via MAGL inhibition reduces LPSinduced nociception through a cannabinoid receptor mechanism of action, while decreasing 2-AG levels in peripheral tissue (possibly in macrophages) by inhibiting DAGL-β reduces LPS-induced nociception by dampening the innate immune response.”
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    CFA administration into a ventral footpad leads to upregulation of CB2 receptors, but not CB2 receptor mRNA in dorsal root ganglia or ipsilateral paw tissue of rats.

    “CFA administration into a ventral footpad leads to upregulation of CB 2 receptors, but not CB 2 receptor mRNA in dorsal root ganglia or ipsilateral paw tissue of rats, suggesting that these receptors play an integral role in the endocannabinoid modulation of chronic inflammatory pain (Hsieh et al, 2011).”
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    The antinociceptive effects of JWH015 are mediated by CB2 receptors and μ opioid receptors (MORs).

    “Unexpectedly, the antinociceptive effects of this drug are mediated by CB 2 receptors and μ opioid receptors (MORs).”
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    The CB2 receptor agonist GW405833 produces antinociceptive effects through a CB1 receptor mechanism of action, while CB2 receptors were dispensible.

    “In another study, the CB 2 receptor agonist GW405833 was reported to produce antinoiceptive effects through CB 1 receptor mechanism of action, while CB 2 receptors were dispensible (Li et al, 2017).”
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    Isobolographic analyses revealed that the interaction of ACPA and DAMGO is infra-additive, indicating that the combination is less effective than either drug by itself.

    “However, isobolographic analyses revealed that the interaction is infra-additive, indicating that the combination is less effective than either drug by itself (Auh et al, 2016).”
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    The dual FAAH-MAGL inhibitor JZL195 reduces mechanical allodynia and thermal hyperalgesia induced by CFA injection.

    “The dual FAAH-MAGL inhibitor JZL195 reduces mechanical allodynia and thermal hyperalgesia induced by CFA injection (Anderson et al, 2014).”
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    Chronic FAAH inhibition reduces CIA-induced paw swelling and joint destruction.

    “Furthermore, chronic FAAH inhibition reduces CIA-induced paw swelling (Kinsey et al, 2011b;Lowin et al, 2015) and joint destruction (Kinsey et al, 2011b).”
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    Wild-type mice treated with URB597 or FAAH-/- mice subjected to CIA show reduced thermal hyperalgesia in the hot plate and tail immersion tests.

    “Wild-type mice treated with URB597 or FAAH ( -/ -) mice subjected to CIA show reduced thermal hyperalgesia in the hot plate and tail immersion tests.”
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    MIA induces chondrocyte death, cartilage degradation, and chronic nociception.

    “MIA induces chondrocyte death, cartilage degradation, and chronic nociception (Burston et al, 2013).”
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    Premisecitation

    Osteoarthritis is a highly prevalent type of arthritis characterized by synovitis and degeneration of articular cartilage and subchondral bone in joints of the hands, knees, hips, and spine.

    “Osteoarthritis is a highly prevalent type of arthritis characterized by synovitis, and degeneration of both articular cartilage and subchondral bone in the joints of the hands, knees, hips, and spine (Goldring and Goldring, 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Goldring and Goldring, 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MIA-induced nociception and joint damage occur ipsilateral, but not contralateral, to the injection site.

    “This nociception and joint damage occur ipsilateral, but not contralateral, to the injection site.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    CB2 and CB1 receptors undergo compensatory changes in the MIA osteoarthritis model and may represent potential targets for novel osteoarthritis treatments.

    “suggesting that these receptors undergo compensatory changes in this osteoarthritis model, and may represent potential targets for novel osteoarthritis treatments (Burston et al, 2013;Malek et al, 2015).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Burston et al, 2013 source

      Not checked in the free run.

    • cites Malek et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The CB2 receptor agonist JWH133 attenuates MIA-induced allodynia and restores weight bearing on the arthritic joint.

    “Furthermore, the CB 2 receptor agonist JWH133 attenuates MIA-induced allodynia and restores weight bearing on the arthritic joint (Burston et al, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Burston et al, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The FAAH inhibitor URB597 reduces MIA-induced mechanical hyperalgesia and restores weight bearing on the arthritic limb.

    “The FAAH inhibitor URB597 reduces MIA-induced mechanical hyperalgesia and restores weight bearing on the arthritic limb (Malek et al, 2015;Schuelert et al, 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Malek et al, 2015 source

      Not checked in the free run.

    • cites Schuelert et al, 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The MAGL inhibitor MJN110 attenuates mechanical allodynia and restores MIA limb weight bearing.

    “The MAGL inhibitor MJN110 also attenuates mechanical allodynia and restores MIA limb weight bearing.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Neuropathic pain often manifests as a spontaneous burning, tingling, or shooting sensation, which can be amplified by noxious and otherwise innocuous mechanical and thermal stimuli.

    “Neuropathic pain often manifests as a spontaneous burning, tingling, or shooting sensation, which can be amplified by noxious (pressure, heat, and cold), and otherwise innocuous (touch and warm or cool temperatures) mechanical and thermal stimuli (Jensen and Finnerup, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jensen and Finnerup, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nerve injury induces hyperexcitability, causing functional alterations such as loss of function of inhibitory neurons in the dorsal horn, and results in neuropathic pain.

    “Nerve injury induces hyperexcitability, thereby causing functional alterations in the neuronal network such as loss of function of inhibitory neurons in the dorsal horn, and results in neuropathic pain (Prescott et al, 2014;Todd, 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Prescott et al, 2014 source

      Not checked in the free run.

    • cites Todd, 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    In preclinical inflammatory pain models, anti-inflammatory treatments including manipulation of the endocannabinoid system are often administered repeatedly for a few days (subchronically).

    “(2) administered repeatedly for a few days (ie, subchronically).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Neuropathic pain pathophysiology is complex and includes functional alterations of the CNS and PNS in addition to neuro-immune interactions.

    “Neuropathic pain pathophysiology is complex and includes functional alterations of the CNS and PNS (Cohen and Mao, 2014) in addition to neuro-immune interactions (Austin and Moalem-Taylor, 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Cohen and Mao, 2014 source

      Not checked in the free run.

    • cites Austin and Moalem-Taylor, 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Premisenone given

    Laboratory animal models that accurately mimic key aspects of clinically reported pain are needed to test candidate therapies.

    “Also, laboratory animal models that accurately mimic key aspects of the pain reported clinically are needed to test candidate therapies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    A great need exists for the development of new efficacious analgesics for neuropathic pain.

    “so a great need exists for the development of new efficacious analgesics.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Acute manipulation of the endocannabinoid system typically reduces pain measures via CB1 receptor.

    “In addition, acute manipulation of the endocannabinoid system typically reduces pain measures via CB 1 receptor.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Although a wide variety of laboratory animal models of nociception have been applied to experimental neuropathic and inflammatory pain procedures, these assays generally have limited ability to reflect fully the complexity of clinical symptoms and comorbidities.

    “Although a wide variety of laboratory animal models of nociception (see Table 1) have been applied to experimental neuropathic and inflammatory pain procedures, these assays generally have limited ability to reflect fully the complexity of clinical symptoms and comorbidities.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisereasoning

    Assessing neuropathic pain behavior in rodents is crucial to validate pain models and new analgesics.

    “Assessing neuropathic pain behavior in rodents is crucial to validate pain models and new analgesics.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The results of preclinical studies highlight potentially important roles of the endocannabinoid system in the pathophysiology of neuropathic pain and potential therapeutic targets to treat these conditions.

    “The results of these studies highlight potentially important roles of the endocannabinoid system in the pathophysiology of neuropathic pain, and potential therapeutic targets to treat these conditions (Figures 1 and 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Figures 1 and 2

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB1-/- mice show a pain-induced increase in time spent in the dark area of the light/dark test and decreased time and travel distance in the open area of the zero-maze apparatus.

    “but rather a pain-induced increase in time spent in the dark area of the light/dark test, and decreased time and travel distance in the open area of the zero-maze apparatus.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nadal et al, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB1-/- mice show a reduction in sucrose preference and home cage activity.

    “Additionally, CB 1 ( -/ -) mice show a reduction in sucrose preference and home cage activity (Rácz et al, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rácz et al, 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Selective CB1 receptor deletion in peripheral nociceptors leads to enhanced pain behavior as well as diminished antinociceptive effects of cannabinoid receptor agonists.

    “Strikingly, selective CB 1 receptor deletion in peripheral nociceptors leads to enhanced pain behavior as well as diminished antinociceptive effects of cannabinoid receptor agonists, suggesting an important role of peripheral CB 1 receptors in neuropathic pain (Agarwal et al, 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Agarwal et al, 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Pain assessments in laboratory animal models provide valuable tools for the mechanistic understanding of neuropathic pain syndromes and remain a key step in the discovery process for new pain medications.

    “Nevertheless, pain assessments in these models provide valuable tools for the mechanistic understanding of neuropathic pain syndromes and remain a key step in the discovery process for new pain medications.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Ceiling effects and other methodological differences between studies may have precluded the detection of enhanced nociceptive behavior in neuropathic pain models.

    “though ceiling effects and other methodological differences between studies may have precluded the detection of enhanced nociceptive behavior.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kinsey et al, 2009 source

      Not checked in the free run.

    • cites Kinsey et al, 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB2-/- mice show exacerbated pain behavior, while CB2 overexpression in the CNS attenuates neuropathic pain.

    “CB 2 ( -/ -) mice show exacerbated pain behavior, while CB 2 overexpression in the CNS attenuates neuropathic pain (Racz et al, 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Racz et al, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mixed CB1/CB2 receptor agonists, CB1-selective receptor agonists, and CB2 receptor-selective agonists suppress increased nociceptive behavior in the CCI, SNL and pSNL models.

    “As shown in Table 5, mixed CB 1 /CB 2 receptor agonists, CB 1 -selective receptor agonists, and CB 2 receptor-selective agonists suppress increased nociceptive behavior in the CCI, spinal nerve ligation (SNL) and partial sciatic nerve ligation (pSNL) models.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 5

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The fatty acid amide PEA, a substrate of FAAH and an endogenous PPARα ligand, produces antinociceptive effects in a rat pSNL model and in a mouse CCI model.

    “In addition, the fatty acid amide PEA, a substrate of FAAH and an endogenous PPARα ligand, produces antinociceptive effects in a rat pSNL model and in a mouse CCI model (Di Cesare Mannelli et al, 2013;Costa et al, 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Di Cesare Mannelli et al, 2013

      Not checked in the free run.

    • cites Costa et al, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In both SNL and pSNL models, the FAAH inhibitor URB597 evoked anti-allodynic as well as anti-hyperalgesic effects.

    “In both SNL and pSNL models, the FAAH inhibitor URB597 evoked anti-allodynic (de Novellis et al, 2011), as well as anti-hyperalgesic effects (Desroches et al, 2008(Desroches et al, , 2014b)).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites de Novellis et al, 2011 source

      Not checked in the free run.

    • cites Desroches et al, 2008 source

      Not checked in the free run.

    • cites Desroches et al, 2014b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FAAH inhibitors produce antinociceptive effects in the CCI model without the development of tolerance upon repeated administration.

    “It is noteworthy that FAAH inhibitors produce antinociceptive effects in the CCI model, without the development of tolerance upon repeated administration (Schlosburg et al, 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schlosburg et al, 2010 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Inhibition of 2-AG hydrolysis or biosynthesis on macrophages and microglia results in a reduction of arachidonic acid and proinflammatory metabolites, which can reduce nociceptive behavior through cannabinoid receptor-independent mechanisms.

    “Thus, inhibition of 2-AG hydrolysis or biosynthesis on macrophages and microglia results in a reduction of arachidonic acid and proinflammatory metabolites, which can reduce nociceptive behavior through cannabinoid receptor-independent mechanisms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    2-AG is the most highly expressed endocannabinoid in the CNS, plays a major role in cannabinoid receptor activation, and represents a rate-limiting precursor of arachidonic acid in the CNS and immune cells.

    “Specifically, as 2-AG is the most highly expressed endocannabinoid in the CNS, it not only plays a major role in cannabinoid receptor activation, but also represents a rate-limiting precursor of arachidonic acid in the CNS and immune cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Selective inhibition of DAGL-β, the biosynthetic enzyme expressed predominantly on macrophages and microglia, reduces pro-inflammatory mediators and reverses nociceptive behavior in a mouse model of CCI.

    “The observation that selective inhibition of DAGL-β, the biosynthetic enzyme expressed predominantly on macrophages and microglia, reduces pro-inflammatory mediators (Hsu et al, 2012), and reverses nociceptive behavior in a mouse model of CCI (Wilkerson et al, 2016a) appears to be at odds with the antinociceptive effects of MAGL inhibitors in this same model.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hsu et al, 2012 source

      Not checked in the free run.

    • cites Wilkerson et al, 2016a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    STZ-induced diabetes produces consistent, long-lasting thermal and mechanical hyperalgesia, in addition to cold and mechanical allodynia, associated with hyperexcitability of nociceptive C fibers in response to mechanical stimuli.

    “STZ-induced diabetes produces consistent, long-lasting thermal and mechanical hyperalgesia, in addition to cold and mechanical allodynia (Courteix et al, 1993), associated with hyperexcitability of nociceptive C fibers in response to mechanical stimuli.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Courteix et al, 1993 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    THC and WIN55,212-2 produce antinociception in rodent STZ-induced peripheral neuropathy.

    “Several studies have demonstrated that THC (Williams et al, 2008) and WIN55,212-2 (Bujalska, 2008;Doğrul et al, 2004;Ikeda et al, 2013;Jahanabadi et al, 2016;Mohammadi-Farani et al, 2010;Ulugol et al, 2004;Vera et al, 2012;Vincenzi et al, 2013) produce antinociception in rodent STZinduced peripheral neuropathy.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Williams et al, 2008 source

      Not checked in the free run.

    • cites Bujalska, 2008 source

      Not checked in the free run.

    • cites Doğrul et al, 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CIPN is a common cause for early cessation of cancer treatment and affects up to 70% of patients receiving chemotherapy.

    “It is a common cause for early cessation of cancer treatment and affects up to 70% of patients receiving chemotherapy (Seretny et al, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Seretny et al, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Chronic low-dose CP55,940 suppressed paclitaxel-induced allodynia in wild-type and CB2-/- mice, but not CB1-/- mice.

    “Notably, chronic low-dose CP55,940 suppressed paclitaxel-induced allodynia in wild-type and CB 2 ( -/ -) mice, but not CB 1 ( -/ -) mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Lower doses of paclitaxel (eg, 0.5, 1, or 2 mg/kg, intraperitoneal) administered on alternate days for four injections elicit thermal and mechanical hyperalgesia as well as allodynia to light touch and cold stimuli.

    “On the other hand, lower doses of paclitaxel (eg, 0.5, 1, or 2 mg/kg, intraperitoneal) administered on alternate days for four injections elicit thermal and mechanical hyperalgesia as well as allodynia to light touch and cold stimuli (Polomano and Bennett, 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Polomano and Bennett, 2001 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mixed CB1/CB2 receptor agonists and CB2 receptor-selective agonists are effective against paclitaxel-induced peripheral neuropathy.

    “It has been reported that mixed CB 1 /CB 2 receptor agonists and CB 2 receptor-selective agonists are effective against paclitaxel-induced peripheral neuropathy (Deng et al, 2015a(Deng et al, , 2015b;;Pascual et al, 2005;Rahn et al, 2008).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Deng et al, 2015a

      Not checked in the free run.

    • cites Pascual et al, 2005 source

      Not checked in the free run.

    • cites Rahn et al, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Selective CB2 receptor agonists produce sustained antinociceptive effects in the paclitaxel model without evidence of tolerance.

    “In contrast, selective CB 2 receptor agonists produce sustained antinociceptive effects in this model without evidence of tolerance (Deng et al, 2015a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Deng et al, 2015a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single injection of paclitaxel (32 mg/kg, intraperitoneal) in rats produces mechanical and thermal hyperalgesia, but does not elicit mechanical allodynia.

    “A single injection of paclitaxel (32 mg/kg, intraperitoneal) in rats produces mechanical and thermal hyperalgesia, but does not elicit mechanical allodynia (Authier et al, 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Authier et al, 2000 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Patients with CIPN experience symptoms of neuropathic pain such as paraesthesia, dysesthesia, allodynia, and hyperalgesia, in addition to numbness.

    “Patients with CIPN experience symptoms of neuropathic pain such as paraesthesia, dysesthesia, allodynia, and hyperalgesia, in addition to numbness (Boyette-Davis et al, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Boyette-Davis et al, 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting neurotoxic effect of chemotherapeutic agents used to treat cancer.

    “Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting neurotoxic effect of chemotherapeutic agents used to treat cancer.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FAAH and MAGL inhibitors reduced cisplatin-induced mechanical and cold allodynia, which are CB1 and CB2 receptors-mediated.

    “Finally, FAAH and MAGL inhibitors reduced cisplatin-induced mechanical and cold allodynia, which are CB 1 and CB 2 receptors-mediated (Guindon et al, 2013;Khasabova et al, 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Guindon et al, 2013 source

      Not checked in the free run.

    • cites Khasabova et al, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AM1710 suppressed the maintenance of mechanical and cold allodynia in the cisplatin model through a CB2 receptor mechanism of action, with no evidence of CB1 receptor involvement.

    “Conversely, AM1710 suppressed the maintenance of mechanical and cold allodynia in the cisplatin model through a CB 2 receptor mechanism of action, with no evidence of CB 1 receptor involvement (Deng et al, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Deng et al, 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rats, 10 daily injections of vincristine (0.02, 0.1, or 0.2 mg/kg, intravenous) with a 2-day drug-free interval after the fifth day induced hyperalgesia and allodynia.

    “In rats, 10 daily injections of vincristine (0.02, 0.1, or 0.2 mg/kg, intravenous) with a 2-day drug-free interval after the fifth day, induced hyperalgesia (Aley et al, 1996), and allodynia (Authier et al, 1999).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Aley et al, 1996 source

      Not checked in the free run.

    • cites Authier et al, 1999 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitroglycerin-induced hyperalgesia in rats is associated with increased activity of both FAAH and MAGL, and increased density of cannabinoid receptors binding sites in the mesencephalon.

    “Another study shows that nitroglycerin-induced hyperalgesia in rats is associated with increased activity of both FAAH and MAGL, and increased density of cannabinoid receptors binding sites in the mesencephalon.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Greco et al, 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preclinical evidence demonstrates co-expression of CB1 receptors and MORs in the periaqueductal gray, and co-administration of HU-210 and morphine into this brain region produces enhanced antinociceptive effects.

    “Moreover, preclinical evidence demonstrates co-expression of CB 1 receptors and MORs in the periaqueductal gray and the co-administration of HU-210 and morphine into this brain region produces enhanced antinociceptive effects (Wilson-Poe et al, 2012, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wilson-Poe et al, 2012, 2013

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    A dysfunction of the endocannabinoid system may contribute to the development of migraine attacks, and modulation of this system can be useful for the treatment of pain associated with migraine.

    “These studies suggest that a dysfunction of the endocannabinoid system may contribute to the development of migraine attacks and modulation of this system can be useful for the treatment of pain associated to migraine.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Greco et al, 2010 source

      Not checked in the free run.

    • cites Greco et al, 2011 source

      Not checked in the free run.

    • cites Nozaki et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subthreshold doses of THC or CP55,940 produce leftward shifts in the antinociceptive dose-response relationships of fentanyl, etorphine, and buprenorphine, with increased shifts for high-efficacy MOR agonists compared with low-efficacy MOR agonists.

    “Likewise, subthreshold doses of THC or CP55,940 produce leftward shifts in the antinociceptive dose-response relationships of fentanyl, etorphine, and buprenorphine, with increased shifts for the highefficacy MOR agonists compared with the low-efficacy MOR agonists (Maguire andFrance, 2014, 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Maguire andFrance, 2014, 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combined peripheral administration of EM-1 and 2-AG attenuates mechanical allodynia produced by intra-articular injection of carrageenan, but does not affect edema.

    “Combined peripheral administration of the endogenous opioid peptide EM-1 and the endocannabinoid 2-AG attenuates mechanical allodynia produced by intra-articular injection of carrageenan, but did not affect edema (Mecs et al, 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mecs et al, 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The MAGL inhibitor MJN110 interacts in a synergistic manner with morphine to reverse allodynia and thermal hyperalgesia in the mouse CCI model, without opioid-induced constipation or cannabinoid subjective effects.

    “The MAGL inhibitor MJN110 interacts in a synergistic manner with morphine to reverse allodynia and thermal hyperalgesia in the mouse CCI model, without opioid-induced constipation or cannabinoid subjective effects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wilkerson et al, 2016b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Within the CNS, opioid administration leads to the activation of microglia via a toll-like receptor (TLR)-4-dependent mechanism, and produces paradoxical aggravation of proinflammatory immune responses.

    “Moreover, an overwhelming amount of evidence demonstrates that within the CNS, opioid administration leads to the activation of microglia via a toll-like receptor (TLR)-4-dependent mechanism, and produces paradoxical aggravation of proinflammatory immune responses (Hutchinson et al, 2007;Watkins et al, 2009).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hutchinson et al, 2007 source

      Not checked in the free run.

    • cites Watkins et al, 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SA-57, a dual FAAH-MAGL inhibitor that inhibits FAAH at considerably lower doses than it inhibits MAGL, interacts in an additive manner with morphine to reverse allodynia in the mouse CCI model.

    “Additionally, SA-57, a dual FAAH-MAGL inhibitor that inhibits FAAH at considerably lower doses than it inhibits MAGL, interacts in an additive manner with morphine to reverse allodynia in the mouse CCI model (Wilkerson et al, 2017), while only producing antinociception in the tetrad assay for cannabimimetic effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wilkerson et al, 2017 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Opioid-cannabinoid combinations lead to enhanced antinociception in laboratory animal pain models but do not increase untoward side effects of opioids, such as respiratory depression, abuse liability or constipation.

    “In summary, opioid-cannabinoid combinations lead to enhanced antinociception in laboratory animal pain models but do not increase untoward side effects of opioids, such as respiratory depression, abuse liability (Gerak and France, 2016) or constipation (Wilkerson et al, 2016b).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gerak and France, 2016 source

      Not checked in the free run.

    • cites Wilkerson et al, 2016b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Within the CNS, CB2 receptor agonists increase the anti-inflammatory cytokine IL-10 and decrease IL-1β.

    “Specifically, it has been found that, within the CNS, CB 2 receptor agonists increase the anti-inflammatory cytokine IL-10, decrease IL-1β (Wilkerson et al, 2012a(Wilkerson et al, , 2012b)), decrease signaling within the AKT-ERK1/2 pathway (Merighi et al, 2012) and reduce mRNA of monocyte chemoattractant protein 1 (MCP-1)/ CCL2 (Deng et al, 2015a).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Wilkerson et al, 2012a

      Not checked in the free run.

    • cites Wilkerson et al, 2012b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent meta-analysis reported strong evidence that cannabinoids produce opioid-sparing effects in preclinical studies, but only a single study of nine clinical studies provided evidence of opioid-sparing effects in humans.

    “Indeed, a recent meta-analysis study reported strong evidence that cannabinoids produce opioid-sparing effects in preclinical studies, but only a single study of nine clinical studies provided evidence of opioid-sparing effects in humans (Nielsen et al, 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nielsen et al, 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a pilot study of chemotherapy-induced neuropathic pain, no statistically significant difference in pain scores was found in the oromucosal-treated group compared to placebo, although five of 16 participants reported a 2-point grade reduction of pain score.

    “In a pilot study of chemotherapy-induced neuropathic pain, no statistically significant difference in pain scores was found in the oromucosal-treated group, as compared to the placebo group, although five of the 16 participants reported a 2-point grade reduction of pain score (Lynch et al, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lynch et al, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A comprehensive meta-analysis shows that medicinal cannabis and cannabinoids effectively alleviate different types of pain, such as neuropathic, fibromyalgia, multiple sclerosis, cancer, diabetic neuropathy, refractory pain due to multiple sclerosis or other neurological conditions, rheumatoid arthritis, noncancer pain, central pain, musculoskeletal problems, and chemotherapy-induced pain.

    “A comprehensive meta-analysis shows that medicinal cannabis and cannabinoids effectively alleviate different types of pain, such as neuropathic, fibromyalgia, multiple sclerosis, cancer, diabetic neuropathy, refractory pain due to multiple sclerosis or other neurological conditions, rheumatoid arthritis, noncancer pain, central pain, musculoskeletal problems, and chemotherapy-induced pain (Whiting”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Whiting et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PF-04457845 was well tolerated in patients, with no evidence of serious adverse events.

    “It is also important to recognize that the highly selective FAAH inhibitor PF-04457845 was well tolerated in the patients, with no evidence of serious adverse events (Huggins et al, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Huggins et al, 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an experimental pain model involving thermal stimuli applied to normal subjects, the combination of morphine and THC showed an enhanced analgesic effect with respect to the affective component of pain, whereas the doses of morphine or THC used alone did not elicit a significant analgesic effect.

    “In this study, the doses of morphine or THC used alone did not elicit a significant analgesic effect, but combination of the drugs showed an enhanced analgesic effect with respect to the affective component of pain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Roberts et al, 2006 source

      Not checked in the free run.

99 of 99

  • The paper relies on this without support.

    A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury.

    “A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury.”

  • The paper relies on this without support.

    The lack of efficacy of conventional pharmacotherapies to reduce pain, and the significant side effects associated with available medications, creates an unmet need that has fueled drug discovery efforts for novel analgesics.

    “Indeed, the lack of efficacy of conventional pharmacotherapies to reduce pain, and the significant side effects associated with available medications, creates an unmet need, which has fueled drug discovery efforts for novel analgesics.”

  • The paper relies on this without support.

    Cannabidiol does not bind cannabinoid receptors.

    “However, as CBD does not bind cannabinoid receptors, this review will not discuss this phytocannabinoid at length.”

  • The paper relies on this without support.

    Preclinical findings in rodent pain models are predictive of clinical efficacy in humans.

    “These experimental limitations must be considered when translating results from preclinical research to the clinic.”

  • The paper relies on this without support.

    Endocannabinoid system components identified in animal models have corresponding roles in human pain conditions.

    “Using complementary genetic and pharmacological approaches, distinct components of the endocannabinoid system (ie, receptors and endocannabinoid-regulating enzymes) have emerged as promising targets to treat neuropathic pain (Table 5; for additional information, Guindon and Hohmann, 2009;Rahn and Hohmann, 2009).”

  • The paper relies on this without support.

    Preclinical antinociceptive effects of cannabinoids in animal pain models predict clinical analgesic efficacy in humans.

    “Overall, these results indicate that the actions of either direct CB 1 /CB 2 receptor agonists or the inhibition of endocannabinoid degradative enzymes are a novel therapeutic avenue to decrease the doses of opioids needed for clinical pain control, and warrants further clinical investigation.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The ECS modulates the HPA axis, cognition, learning and memory, intestinal-barrier function, inflammation, and energy metabolism.

    “The ECS modulates a multitude of physiological processes, including the HPA axis (241), cognition, learning and memory (242), intestinal-barrier function (243), inflammation (244), energy metabolism (245), among others (reviewed recently (239)).”

    From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [244]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Inflammogens described as causing both antinociception and pain

    Minor

    The paper says carrageenan and LPS induce antinociception, but later says LPS induces pain that cannabinoid agonists attenuate.

  • Proposed arthritis mechanism reverses the reported effect

    Minor

    The summary says cannabinoids may reduce inflammation by releasing proinflammatory cytokines and matrix-degrading enzymes, whereas the preceding results say cannabinoids attenuate their production.

2 of 2

The citation lists haven’t been fetched yet

References 315 · Cited by 301

Research works printed but not linked: 1

  1. Ignatowska-Jankowska BM, Baillie GL, Kinsey S, Crowe M, Ghosh S, Owens RA et al (2015c). A Cannabinoid CB1 receptor-positive allosteric modulator reduces neuropathic pain in the mouse with no psychoactive effects. Neuropsychopharmacology 40: 2948–2959. · DOI

Authors
Donvito, G., Nass, S. R., Wilkerson, J. L., Curry, Z. A., Schurman, L. D., Kinsey, S. G., & Lichtman, A. H.
Affiliations
  • Virginia Commonwealth University (US)
  • West Virginia University (US)
Corresponding author
Lichtman, Aron H
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2017-08-31
Volume
43
Issue
1
Pages
52-79
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2017.204
PMC
PMC5719110
OpenAlex
W2752069735
Cited by
301
References
315
Citations by year
2026: 24 · 2025: 31 · 2024: 35 · 2023: 26 · 2022: 35 · 2021: 57 · 2020: 46 · 2019: 29 · 2018: 17 · 2017: 1
FWCI
3.23
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • The Research Repository @ WVU (West Virginia University) (submittedVersion)
Funders
  • National Institutes of Health (1r03da038714-01)
  • National Institute on Drug Abuse (R01DA039942, P01DA009789, R01DA032933, P30DA033934, R03 DA038714, F32DA038493, T32DA007027)
  • National Institute of Neurological Disorders and Stroke (F31NS095628)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R15AR066806)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
Keywords
endocannabinoid system, cannabinoid receptors, cannabinoid receptor agonists, fatty acid amide hydrolase, monoacylglycerol lipase, 2-arachidonoylglycerol, opioid-sparing effect, antinociception, inflammatory pain, neuropathic pain, medical cannabis, analgesic targets
MeSH terms
Animals, Humans, Inflammation, Neuralgia, Analgesics, Non-Narcotic, Receptors, Cannabinoid, Drug Discovery, Cannabinoid Receptor Modulators, Endocannabinoids

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

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