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 µ-
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 µ-
opioid receptor. Thus, CB1R agonists may enable
opioid dose reduction and avoid
opioid-related side effects.SIGNIFICANCE STATEMENT One of the most cited needs for patients with
abdominal pain are safe and effective treatment options. The effectiveness of
opioids in the management of
abdominal pain is undermined by severe adverse side effects. Therefore, strategies to replace
opioids or reduce the doses of
opioids to suppress
abdominal pain is needed. This study in mice demonstrates that
cannabinoid 1 receptor (CB1R) agonists inhibit visceral sensation. Furthermore, a combination of subanalgesic doses of µ-
opioid receptor agonist and CB1R agonist markedly reduce
abdominal pain without causing the side effects of high-dose
opioids. Thus, CB1R agonists, alone or in combination with low-dose
opioids, may be a novel and safe treatment strategy for
abdominal pain.