Anti-nociceptive interactions between opioids and a cannabinoid receptor 2 agonist in inflammatory pain

Abstract

The cannabinoid 1 receptor and cannabinoid 2 receptor can both be targeted in the treatment of pain; yet, they have some important differences. Cannabinoid 1 receptor is expressed at high levels in the central nervous system, whereas cannabinoid 2 receptor is found predominantly, although not exclusively, outside the central nervous system. The objective of this study was to investigate potential interactions between cannabinoid 2 receptor and the mu-opioid receptor in pathological pain. The low level of adverse side effects and lack of tolerance for cannabinoid 2 receptor agonists are attractive pharmacotherapeutic traits. This study assessed the anti-nociceptive effects of a selective cannabinoid 2 receptor agonist (JWH-133) in pathological pain using mice subjected to inflammatory pain using the formalin test. Furthermore, we examined several ways in which JWH-133 may interact with morphine. JWH-133 produces dose-dependent anti-nociception during both the acute and inflammatory phases of the formalin test. This was observed in both male and female mice. However, a maximally efficacious dose of JWH-133 (1 mg/kg) was not associated with somatic withdrawal symptoms, motor impairment, or hypothermia. After eleven once-daily injections of 1 mg/JWH-133, no tolerance was observed in the formalin test. Cross-tolerance for the anti-nociceptive effects of JWH-133 and morphine were assessed to gain insight into physiologically relevant cannabinoid 2 receptor and mu-opioid receptor interaction. Mice made tolerant to the effects of morphine exhibited a lower JWH-133 response in both phases of the formalin test compared to vehicle-treated morphine-naïve animals. However, repeated daily JWH-133 administration did not cause cross-tolerance for morphine, suggesting opioid and cannabinoid 2 receptor cross-tolerance is unidirectional. However, preliminary data suggest co-administration of JWH-133 with morphine modestly attenuates morphine tolerance. Isobolographic analysis revealed that co-administration of JWH-133 and morphine has an additive effect on anti-nociception in the formalin test. Overall these findings show that cannabinoid 2 receptor may functionally interact with mu-opioid receptor to modulate anti-nociception in the formalin test.

Δ9-tetrahydrocannabinol Attenuates Oxycodone Self-Administration Under Extended Access Conditions

“…The study also showed that sensation for a noxious stimulus, as classic preclinical model of analgesic activity, was additively diminished by the co-administration of THC with oxycodone compared with either drug administered alone. Prior work has shown antinociceptive interactions between muopioid and cannabinoid receptor ligands in formalin test of inflammatory pain (Yuill et al, 2017) and in nociception rhesus monkeys (Li et al, 2008). The present study extends those results to the interaction of THC with the effects of the prescription opioid oxycodone.…”

Slowly Signaling G Protein–Biased CB2 Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence

“…AM1241 produced a modest enhancement of opioid-mediated antinociception in the hotplate test and in a test of mechanical sensitivity in tumor-bearing rats (Zhang et al, 2016); however, tolerance developed to the antiallodynic effects of the combination treatment assessed with mechanical but not thermal (hot plate) stimulation, suggesting that therapeutic benefit of the adjunctive treatment may be ligand-and/or modalitydependent. Coadministration of CB2 agonist JWH133 also exhibited opioid-sparing effects in the formalin model of inflammatory pain (Yuill et al, 2017). The mechanism underlying these therapeutically advantageous properties remains incompletely understood.…”

Cannabinoid-2 Agonism with AM2301 Mitigates Morphine-Induced Respiratory Depression

“…Cannabinoids are analgesic in several models of pain 5,[7][8][9][10][11] and act synergistically with opioids, 12 allow-ing for opioid sparing. Medicinal cannabis patients cite pain relief and opioid replacement as top reasons for use.…”

“…14 In contrast, preclinical studies report that cannabinoid-2 receptor (CB2R) agonism reduces acute, chronic, and inflammatory pain without psychoactive side effects. [8][9][10][11] However, the actions of cannabinoid compounds on respiration and interactions with opioid respiratory depression are unknown.…”