Opioid and cannabinoid synergy in a mouse neuropathic pain model

Br J Pharmacol. 2016 Aug;173(16):2521-31. doi: 10.1111/bph.13534. Epub 2016 Jul 13.


Background and purpose: Clinical 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 approach: C57BL/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 results: The opioid agonist morphine reduced CCI-induced mechanical and cold allodynia and produced motor incoordination, in a dose-dependent 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 implications: These 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.

MeSH terms

  • Analgesics, Opioid / antagonists & inhibitors
  • Analgesics, Opioid / therapeutic use*
  • Animals
  • Cannabinoids / therapeutic use*
  • Disease Models, Animal*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morphine / administration & dosage
  • Morphine / pharmacology
  • Neuralgia / drug therapy*
  • Neuralgia / surgery
  • Structure-Activity Relationship


  • Analgesics, Opioid
  • Cannabinoids
  • Morphine