Opioid and cannabinoid synergy in a mouse neuropathic pain model

Abstract

BACKGROUND AND PURPOSEClinical studies have reported that pan-cannabinoid receptor agonists may have efficacy in neuropathic pain states and that this might be enhanced by co-administration with opioids. While cannabinoid-opioid analgesic synergy has been demonstrated in animal models of acute pain, it has not been examined in neuropathic pain models. We examined the effect of combination treatment with cannabinoid and opioid receptor agonists on allodynia and side effects in a nerve injury-induced neuropathic pain model. EXPERIMENTAL APPROACHC57BL/6 mice were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of systemic administration of morphine and the pan-cannabinoid receptor agonist, WIN55212, on allodynia and side effects were examined at 7-10 days post-CCI surgery. Isobolographic analysis was used to determine whether the effects of the combination were synergistic. KEY RESULTSThe opioid agonist morphine reduced CCI-induced mechanical and cold allodynia and produced motor incoordination, in a dosedependent manner. WIN55212 reduced CCI-induced allodynia and produced motor incoordination, catalepsy and sedation, in a dose-dependent manner, as we have observed previously. When administered together, WIN55212 and morphine reduced allodynia in a synergistic manner but had only an additive effect on motor incoordination. CONCLUSIONS AND IMPLICATIONSThese findings indicate that administration of a combination of a non-selective opioid and cannabinoid receptor agonist synergistically reduces nerve injury-induced allodynia, while producing side effects in an additive manner. This suggests that this combination treatment has an improved anti-allodynic potency and therapeutic index in a neuropathic pain model. AbbreviationsCCI, chronic constriction injury; MPE, maximum possible effect; PWT, paw withdrawal threshold; THC, Δ 9

A systematic review of the analgesic efficacy of cannabinoid medications in the management of acute pain

“…A small body of evidence has accumulated that points toward, a potential synergistic interaction between cannabinoids and opioids 21,22 that results in improved pain relief. Studies included in this systematic review that assessed the analgesic efficacy of cannabinoids when combined with opioids, 13,14 failed to demonstrate any additional analgesic benefit when used together.…”

The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesia in mice

“…Despite the benefits of MAGL inhibition, chronic administration of high‐dose JZL184 or KML29 induces physical dependence and cross‐tolerance to cannabinoid receptor agonists and down‐regulates and desensitizes CB 1 receptors (Ignatowska‐Jankowska et al, ; Schlosburg et al, ). To circumvent the effects of high doses and maximize analgesia, research has focused on using lower doses of endocannabinoid modulators in combination with other analgesics (Gunduz et al, ; Grim et al, ; Kazantzis et al, ). For example, the combined pharmacological inhibition of MAGL and COX1 and 2 synergistically attenuated mechanical allodynia and additively attenuated cold allodynia (Crowe et al, ), indicating that MAGL might be a good candidate for combination therapy.…”

The dynamic interaction between pain and opioid misuse

“…Under this type of adjunctive therapy, tolerance and dose escalation can be prevented, and overall opioid consumption is substantially reduced (Smith et al, ; Haroutounian et al, ). Analgesic synergy has been observed across a wide variety of cannabinoid and opioid agonists, species and administration routes (Cichewicz and McCarthy, ; Roberts et al, ; Kazantzis et al, ). The mechanisms of this generalized synergy are not completely understood, although there are several points of crosstalk between these receptors including overlapping G‐protein signalling cascades and possible hetero‐dimerization (Scavone et al, ).…”