Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury
Open accessAbstract
BACKGROUND: Cannabinoids induce analgesia by acting on cannabinoid receptor (CBR) types 1 and/or 2. However, central nervous system side effects and antinociceptive tolerance from CBR1 limit their clinical use. CBR2 exist on spinal glia and perivascular cells, suggesting an immunoregulatory role of these receptors in the central nervous system. Previously, the authors showed that spinal CBR2 activation reduces paw incision hypersensitivity and glial activation. This study tested whether CBR2 are expressed in glia and whether their activation would induce antinociception, glial inhibition, central side effects, and antinociceptive tolerance in a neuropathic rodent pain model. METHODS: Rats underwent L5 spinal nerve transection or sham surgery, and CBR2 expression and cell localization were assessed by immunohistochemistry. Animals received intrathecal injections of CBR agonists and antagonists, and mechanical withdrawal thresholds and behavioral side effects were assessed. RESULTS: Peripheral nerve transection induced hypersensitivity, increased expression of CR3/CD11b and CBR2, and reduced ED2/CD163 expression in the spinal cord. The CBR2 were localized to microglia and perivascular cells. Intrathecal JWH015 reduced peripheral nerve injury hypersensitivity and CR3/CD11b expression and increased ED2/CD163 expression in a dose-dependent fashion. These effects were prevented by intrathecal administration of the CBR2 antagonist (AM630) but not the CBR1 antagonist (AM281). JWH015 did not cause behavioral side effects. Chronic intrathecal JWH015 treatment did not induce antinociceptive tolerance. CONCLUSIONS: These data indicate that intrathecal CBR2 agonists may provide analgesia by modulating the spinal immune response and microglial function in chronic pain conditions without inducing tolerance and neurologic side effects.
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CP55,940 reversed mechanical allodynia in the L5 spinal nerve transection model 1 h following a second intrathecal injection, although this dosing paradigm was also associated with motor effects.
“CP55,940 reversed mechanical allodynia in this model 1 h following a second intrathecal injection, although this dosing paradigm was also associated with motor effects.96”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [96]
CB2 receptor immunoreactivity is increased in the ipsilateral dorsal horn following L5 spinal nerve transection.
“CB2 receptor immunoreactivity96 is increased in the ipsilateral dorsal horn following L5 spinal nerve transection (L5-SNT).97”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [96]
Intrathecal JWH015 dose-dependently suppressed behavioral hypersensitivity following a second injection, indicating a cumulative anti-allodynic effect of this drug.
“Intrathecal JWH015 dose-dependently suppressed behavioral hypersensitivity following a second injection, indicating a cumulative anti-allodynic effect of this drug.”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [96]
Co-localization of CB2 immunoreactivity with markers of microglia and perivascular cells was observed on day 4 post-surgery after L5 spinal nerve transection.
“Importantly, co-localization of CB2 immunoreactivity with markers of microglia and perivascular cells was observed on day 4 post-surgery.96”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [96]
Intrathecal JWH015 reduced SNT-induced increases in activated microglia in a CB2-dependent manner, supporting a role for nonneuronal CB2 receptors in anti-hyperalgesic effects of CB2 agonists.
“Intrathecal JWH015 reduced SNT-induced increases in activated microglia in a CB2-dependent manner, further supporting a role for nonneuronal CB2 receptors in anti-hyperalesic effects of CB2 agonists. 96”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [96]
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- Authors
- Romero-Sandoval, A., Nutile-McMenemy, N., & DeLeo, J. A.
- Affiliations
- Dartmouth College (US)
- Laboratory Manager, Department of Anesthesiology, Neuroscience Center at Dartmouth, Dartmouth Medical School, Dartmouth College, Lebanon, New Hampshire.
- Venue
- Anesthesiology
- Published
- 2008-04-01
- Volume
- 108
- Issue
- 4
- Pages
- 722-734
- ISSN
- 0003-3022 (ISSN-L)
- PMC
- PMC2647363
- OpenAlex
- W1980780117
- Cited by
- 168
- References
- 56
- Citations by year
- 2025: 9 · 2024: 5 · 2023: 8 · 2022: 5 · 2021: 6 · 2020: 6 · 2019: 4 · 2018: 7 · 2017: 12 · 2016: 6 · 2015: 13 · 2014: 11 · 2013: 14 · 2012: 15
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Anesthesiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (DA 11276, R01DA011276)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Keywords
- cannabinoid receptor type 2, microglia, perivascular cells, peripheral nerve injury, neuropathic pain, antinociception, antinociceptive tolerance, AM630, AM281, CD11b, CD163, spinal cord, intrathecal administration, analgesia
- MeSH terms
- Animals, Behavior, Animal, Cyclohexanols, Drug Tolerance, Indoles, Male, Oligodendroglia, Pain Measurement, Peripheral Nerves, Spinal Cord, Rats, Sprague-Dawley, Microglia, Receptor, Cannabinoid, CB2, Rats, Peripheral Nerve Injuries
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