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Endogenous cannabinoid modulation of restraint stress‐induced analgesia in thermal nociception
Author(s) -
Atwal Nicholas,
Winters Bryony L.,
Vaughan Christopher W.
Publication year - 2020
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14884
Subject(s) - endocannabinoid system , naltrexone , endogenous opioid , nociception , cannabinoid receptor , cannabinoid , pharmacology , antagonist , hot plate test , opioid , opioid antagonist , chemistry , fatty acid amide hydrolase , cannabinoid receptor antagonist , am251 , opioid receptor , medicine , receptor , (+) naloxone , biochemistry
It is thought that endogenous cannabinoids have a role in the analgesia induced by specific forms of stress. We examined if the role of endogenous cannabinoids is also dependent upon the mode of nociception, and whether this could be altered by drugs which block their enzymatic degradation. In C57BL/6 mice, restraint stress produced analgesia in the hot‐plate and plantar tests, two thermal pain assays that engage distinct supraspinal and spinal nociceptive pathways. Stress‐induced analgesia in the hot‐plate test was abolished by pre‐treatment with the opioid receptor antagonist naltrexone but was unaffected by the cannabinoid receptor antagonist 1‐(2,4‐Dichlorophenyl)‐5‐(4‐iodophenyl)‐4‐methyl‐N‐4‐morpholinyl‐1H‐pyrazole‐3‐carboxamide (AM281). By contrast, stress‐induced analgesia in the plantar test was abolished by pre‐treatment with naltrexone plus AM281, but not by either antagonist individually. Remarkably, inhibiting the breakdown of endocannabinoids, with the dual fatty acid amide hydrolase and monoacylglycerol lipase inhibitor JZL195, rescued stress‐induced analgesia in the hotplate test when endogenous opioid signalling was blocked by naltrexone. Furthermore, JZL195 recruited analgesia induced by sub‐threshold restraint stress in both thermal pain assays. These findings indicate the role of endocannabinoids in stress‐induced analgesia differs with the type of thermal pain behaviour. However, by inhibiting their breakdown, endocannabinoids can be recruited to substitute for endogenous opioid signalling when their activity is blocked, indicating a degree of redundancy between opioid and cannabinoid systems. Together these data suggest targeting endocannabinoid breakdown could provide an alternative, or adjuvant to mainstream analgesics such as opioids.