Cannabinoid 1 and mu-Opioid Receptor Agonists Synergistically Inhibit Abdominal Pain and Lack Side Effects in Mice

While effective in treating abdominal pain, opioids have significant side effects. Recent legalization of cannabis will likely promote use of cannabinoids as an adjunct or alternative to opioids, despite a lack of evidence. We aimed to investigate whether cannabinoids inhibit mouse colonic nociception, alone or in combination with opioids at low doses. Experiments were performed on C57BL/6 male and female mice. Visceral nociception was evaluated by measuring visceromotor responses (VMR), afferent nerve mechanosensitivity in flat-sheet colon preparations, and excitability of isolated DRG neurons. Blood oxygen saturation, locomotion, and defecation were measured to evaluate side effects. An agonist of cannabinoid 1 receptor (CB1R), arachidonyl-2'-chloroethylamide (ACEA), dose-dependently decreased VMR. ACEA and HU-210 (another CB1R agonist) also attenuated colonic afferent nerve mechanosensitivity. Additionally, HU-210 concentration-dependently decreased DRG neuron excitability, which was reversed by the CB1R antagonist AM-251. Conversely, cannabinoid 2 receptor (CB2R) agonists did not attenuate VMR, afferent nerve mechanosensitivity, or DRG neuron excitability. Combination of subanalgesic doses of CB1R and mu-opioid receptor agonists decreased VMR; importantly, this analgesic effect was preserved after 6 d of twice daily treatment. This combination also attenuated afferent nerve mechanosensitivity and DRG neuron excitability, which was inhibited by neuronal nitric oxide synthase and guanylate cyclase inhibitors. This combination avoided side effects (decreased oxygen saturation and colonic transit) caused by analgesic dose of morphine. Activation of CB1R, but not CB2R, decreased colonic nociception both alone and in synergy with m-opioid receptor. Thus, CB1R agonists may enable opioid dose reduction and avoid opioid-related side effects.

Automated summary

Although lacking evidence, cannabis may be used as an adjunct or alternative to opioids. This study found that CB1R agonists can reduce colonic nociception in mice, while CB2R agonists do not have this effect. Combining CB1R and opioid agonists can alleviate pain responses and reduce side effects, which may help in reducing opioid dosage.