Reduction in Opioid- and Cannabinoid-Induced Antinociception in Rhesus Monkeys after Bilateral Lesions of the Amygdaloid Complex
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The amygdaloid complex is a prominent temporal lobe region that is associated with "emotional" information processing. Studies in the rodent have also recently implicated the amygdala in the processing and modulation of pain sensation, the experience of which involves a considerable emotional component in humans. In the present study, we sought to establish the relevance of the amygdala to pain modulation in humans by investigating the contribution of this region to antinociceptive processes in nonhuman primates. Using magnetic resonance imaging guidance, the amygdaloid complex was lesioned bilaterally in six rhesus monkeys (Macaca mulatta) through microinjection of the neurotoxin ibotenic acid. This procedure resulted in substantial neuronal cell loss in all nuclear subdivisions of this structure. In awake unoperated control monkeys, systemic administration of the prototypical opioid morphine or the cannabinoid receptor agonist WIN55,212-2 produced dose-dependent antinociception on a warm-water tail-withdrawal assay. The antinociceptive effects of each drug were reversible with an appropriate antagonist. In monkeys with bilateral amygdala lesions, however, the antinociceptive effects of each drug were significantly reduced. These results constitute the first causal data demonstrating the necessity of neurons in a specific brain region for the full expression of opioid- and cannabinoid-induced antinociception in the primate. Because our amygdala-lesioned monkeys exhibited both a reduction in antinociception and a reduction in behavioral indices of fear (Emery et al., 2001), the possibility should be considered that, in the primate, "antinociceptive circuitry" and "fear circuitry" overlap at the level of the amygdala.
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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).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Manning et al, 2001
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Weston, C. S. E. (2014) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2014.00037 · Cited by 114 · see citing works
“Nevertheless, lesions to the amygdala do not affect pain sensitivity levels nor latency of pain responses (129,234,235), so the amygdala may mediate chronic or high-level pain-related functions.”
BackgroundAltered central μ-opioid receptor binding after psychological trauma
Liberzon, I., Taylor, S. F., Phan, K. L., Britton, J. C., Fig, L. M., Bueller, J. A., Koeppe, R. A., & Zubieta, J.-K. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.06.021 · Cited by 118 · see citing works
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Manning, B. H., Martin, W. J., & Meng, I. D. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00356-7 · Cited by 94 · see citing works
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“, 1992) and injection of morphine in the amygdala produces antinociception (Manning et al., 2001).”
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Supraspinal modulation of pain by cannabinoids: the role of GABA and glutamate
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Role of the basolateral nucleus of the amygdala in endocannabinoid-mediated stress-induced analgesia
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“…mesylate (WIN 55,212)] have antinociceptive effects when administered alone (Vivian et al., 1998; Ko and Woods, 1999; Manning et al., 2001), and acute administration of D9-THC enhances the antinociceptive effects of morphine (Li et al., 2008).”
BackgroundCurrent evidence for a modulation of low back pain by human genetic variants
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“Most behavioral effects of exogenously applied cannabinoids (Manning et al. 2001; Pertwee 2001) are mediated by the Gi/o protein–coupled cannabinoid type 1 (CB1) receptor (Zimmer et al. 1999), which is highly expressed in many brain regions, including the amygdala (Herkenham 1995).”
BackgroundCannabidiol increases the nociceptive threshold in a preclinical model of Parkinson's disease
Nascimento, G. C., Ferrari, D. P., Guimarães, F. S., Bel, E. A. D., Bortolanza, M., & Ferreira‐Junior, N. C. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107808 · Cited by 67 · see citing works
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Opioids Inhibit Lateral Amygdala Pyramidal Neurons by Enhancing a Dendritic Potassium Current
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“, 1999 ; Manning et al .”
Cannabinoid receptors and pain
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Perioperative pain therapy in opioid abuse
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Affective analgesia following the administration of morphine into the amygdala of rats
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“Recent studies have reported that bilateral lesions of the central nucleus of the amygdala can reduce cannabinoid-induced antinociceptive effects.(31,32) Unilateral intra-BLA microinjection of a single dose of a cannabi-”
BackgroundCannabinoid Receptors and Their Relationship With Chronic Pain: A Narrative Review
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“In this study, anandamide (endogenous cannabinoid) and WIN55 (cannabinoid receptor agonist) both showed dose-dependent antinociceptive effects [2].”
BackgroundThe medial temporal lobe in nociception: a meta-analytic and functional connectivity study
Ayoub, L. J., Barnett, A. J., Leboucher, A., Golosky, M., McAndrews, M. P., Seminowicz, D. A., & Moayedi, M. (2019) · Pain · doi:10.1097/j.pain.0000000000001519 · Cited by 42 · see citing works
Endocannabinoid activation of the TRPV1 ion channel is distinct from activation by capsaicin
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“In particular, previous studies have demonstrated that cannabinoids, such as AEA and Δ9-tetrahydrocannabinol, exert antinociceptive effects in rhesus monkeys (5, 6).”
BackgroundFunctional imaging and the neural systems of chronic pain
Mackey, S., & Maeda, F. (2004) · Neurosurgery Clinics of North America · doi:10.1016/j.nec.2004.03.001 · Cited by 40 · see citing works
Endogenous opiates and behavior: 2001
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Huge, V., Rammes, G., Beyer, A., Zieglgänsberger, W., & Azad, S. C. (2008) · European Journal of Pain · doi:10.1016/j.ejpain.2008.03.010 · Cited by 38 · see citing works
“The ‘‘antinociceptive circuitry” and the ‘‘fear circuitry” seem to overlap at the level of the amygdala (Manning et al., 2001; Nestler, 2002).”
BackgroundHaghparast, A., Ghalandari-Shamami, M., & Hassanpour-Ezatti, M. (2012) · Brain Research · doi:10.1016/j.brainres.2012.06.023 · Cited by 36 · see citing works
“Manning et al. (2003) demonstrated that the antinociceptive effect of systemically administered morphine is strongly reduced by excitotoxin-induced lesions of the amygdala in both rats and rhesus monkeys (Manning et al., 2001, 2003).”
BackgroundJage, J., Willweber-Strumpf, A., & Maier, C. (2005) · Der Schmerz · doi:10.1007/s00482-005-0426-7 · Cited by 31 · see citing works
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“Manning et al. (2001) showed that antinociceptive effect of the non-selective cannabinoid CB1/CB2 receptor agonist (WIN55,212-2) was reduced in rhesus monkeys with large bilateral lesions of the amygdaloid complex.”
Pharmacotherapy in fibromyalgia (FM) — Implications for the underlying pathophysiology
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Tuberoinfundibular peptide of 39 residues (TIP39) signaling modulates acute and tonic nociception
Dimitrov, E. L., Petrus, E., & Usdin, T. B. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.08.004 · Cited by 26 · see citing works
“The BLA is also necessary for peripherally administered cannabinoids to have an effect on descending modulation of nociception (Manning et al., 2001).”
BackgroundBDNF parabrachio-amygdaloid pathway in morphine-induced analgesia
Sarhan, M., Pawlowski, S. A., Barthas, F., Yalçın, İ., Kaufling, J., Dardente, H., Zachariou, V., Dileone, R., Barrot, M., & Veinante, P. (2013) · The International Journal of Neuropsychopharmacology · doi:10.1017/s146114571200168x · Cited by 25 · see citing works
“The CeA is necessary for the expression of the morphine analgesic properties as evidenced by lesion studies in rodents and primates (Manning and Mayer, 1995; Manning et al., 2001) and morphine suppresses electrophysiological responses to nociceptive stimulus in CeAprojecting PB neurons and in CeA neurons (Huang et al.”
BackgroundKalbasi Anaraki, D., Sianati, S., Sadeghi, M., Ghasemi, M., Javadi, P., Ejtemaei Mehr, S., & Dehpour, A. R. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.02.055 · Cited by 22 · see citing works
Anästhesie und Analgesie bei Suchtpatienten
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Neurometabolic correlates of depression and disability in episodic cluster headache
Seifert, C. L., Valet, M., Pfaffenrath, V., Boecker, H., Rüther, K. V., Tölle, T. R., & Sprenger, T. (2010) · Journal of Neurology · doi:10.1007/s00415-010-5704-3 · Cited by 22 · see citing works
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Neural circuit remodeling and structural plasticity in the cortex during chronic pain
Kim, W., & Kim, S. K. (2016) · Korean Journal of Physiology and Pharmacology · doi:10.4196/kjpp.2016.20.1.1 · Cited by 19 · see citing works
“It is also known to be deeply involved in the processing of the emotional component of pain, probably through a modulatory role upon major supraspinal pain control centers [33].”
BackgroundCannabinoids in anaesthesia and pain therapy
Azad, S. C., & Rammes, G. (2005) · Current Opinion in Anaesthesiology · doi:10.1097/01.aco.0000174959.05383.9c · Cited by 19 · see citing works
Anabolic–androgenic steroid effects on nociception and morphine antinociception in male rats
Tsutsui, K., Wood, R. I., & Craft, R. M. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.04.023 · Cited by 16 · see citing works
“…cumulative dose of up to 18 mg/kg. Cumulative dosing with doses spaced 1/4 to ½ log unit apart is often used in tests of acute antinociception to yield complete dose-effect curves in as few doses as possible (Manning et al., 2001; Stoffel et al., 2003; Morgan et al., 2006; Fischer et al., 2010).”
Resilience to fear: The role of individual factors in amygdala response to stressors
Fonseca, R., Madeira, N., & Simões, C. R. B. (2020) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2020.103582 · Cited by 16 · see citing works
Azad, S. C., Huge, V., Schöps, P., Hilf, C., Beyer, A., Dodt, H., Rammes, G., & Zieglgänsberger, W. (2004) · Der Schmerz · doi:10.1007/s00482-004-0342-2 · Cited by 15 · see citing works
Effects of combined THC and heroin vapor inhalation in rats
Gutierrez, A., Nguyen, J. D., Creehan, K. M., Paydar, M. J., Grant, Y., & Taffe, M. A. (2021) · Psychopharmacology · doi:10.1007/s00213-021-05904-w · Cited by 14 · see citing works
Efficacy of cannabinoids in fibromyalgia: a literature review
Anaya, H. J. M., Ortiz, M. P. T., Valencia, D. H. F., & Ribero, O. F. G. (2021) · Colombian Journal of Anesthesiology · doi:10.5554/22562087.e980 · Cited by 13 · see citing works
“(44-46) The results have shown that cannabinoids have an effect on pain modulation, although it”
BackgroundDistinct pathways for norepinephrine‐ and opioid‐triggered antinociception from the amygdala
Maire, J. J., Close, L. N., Heinricher, M. M., & Selden, N. R. W. (2015) · European Journal of Pain · doi:10.1002/ejp.708 · Cited by 12 · see citing works
“Amygdala lesions that include the CeA attenuate the analgesic effects of systemically administered morphine, and CeA neurons respond to l-opioid agonists (Manning et al., 2001; Zhu and Pan, 2004).”
BackgroundQiao, H., Gao, Y., Huang, Q., & Jia, R. (2019) · Brain and Behavior · doi:10.1002/brb3.1506 · Cited by 11 · see citing works
“The role for this structure in modulating pain sensation is well-supported by many different anatomical, behavioral, and physiological research efforts (Berman et al., 2006; Mayer et al., 2005; Naliboff et al., 2003).”
BackgroundUnveiling the link between chronic pain and misuse of opioids and cannabis
Dagher, M., Alayoubi, M., Sigal, G. H., & Cahill, C. M. (2024) · Journal of Neural Transmission · doi:10.1007/s00702-024-02765-3 · Cited by 11 · see citing works
“…properties has been demonstrated in many preclinical studies showing agonism of CB1 and CB2 receptors result in anti-inflammatory nociceptive outcomes (Calignano, La Rana et al. 1998; Fox et al. 2001; Gühring et al. 2001; Manning et al. 2001; Guin-don and Hohmann 2008; Kinsey et al. 2011).”
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Determining Brain Mechanisms that Underpin Analgesia Induced by the Use of Pain Coping Skills
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Pain and Paresthesia in Parkinson's Disease
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“The amygdala seems to play an important role in the anxiogenic aspect of pain and in fear-conditioned learning (Manning et al., 2001), whereas the hypothalamus and the periaqueductal grey participate in humoral and vegetative responses triggered by nociceptive stimulations (Chamberlin and Saper, 1992; Malick et al.”
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“44 FAAH and monoacylglycerol lipase were expressed in key amygdala regions, indicating an intrinsic deactivation mechanism of AEA and 2-AG.”
Background
- Authors
- Manning, B. H., Merin, N. M., Meng, I. D., & Amaral, D. G.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- University of California, Davis (US)
- University of California, San Francisco (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-10-15
- Volume
- 21
- Issue
- 20
- Pages
- 8238-8246
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6763858
- OpenAlex
- W1723736148
- Cited by
- 88
- References
- 71
- Citations by year
- 2026: 1 · 2024: 2 · 2022: 1 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 4
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Life Sciences Research Foundation
- Medical Research Council Canada
- National Institutes of Health (00169, RR00169)
- U.S. Public Health Service
- Medical Research Council
- National Institute of Mental Health (MH-41479, R01MH041479, R37MH057502, R01MH057502, R37MH041479, MH 57502)
- National Institute of Neurological Disorders and Stroke (NS 10816, F32NS010816)
- National Center for Research Resources (P51RR000169, RR-00169)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Keywords
- amygdala, antinociception, opioid analgesia, cannabinoid analgesia, morphine, WIN 55,212-2, ibotenic acid lesions, rhesus monkeys, pain modulation, fear circuitry, emotional processing
- MeSH terms
- Amygdala, Analgesics, Animals, Behavior, Animal, Cannabinoids, Dose-Response Relationship, Drug, Fear, Ibotenic Acid, Macaca mulatta, Magnetic Resonance Imaging, Male, Microinjections, Morphine, Morpholines, Naphthalenes, Narcotics, Neurons, Pain Measurement, Reaction Time, Wakefulness, Benzoxazines
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