Activation of
cannabinoid receptors (CB(1), CB(2) and GPR(55)) produces
analgesic effects in several experimental
pain models, including
visceral pain arising from the gastrointestinal tract. We assessed the role of CB(1), CB(2), and GPR(55) receptors and the endogenous
cannabinoid system on basal
pain responses and acute
mechanical hyperalgesia during colorectal distension (CRD) in rodents. The effects of
cannabinoid receptor agonists and antagonists on
pain-related responses to CRD were assessed in rats and in wild-type and CB(1) receptor knock-out mice. The dual CB(1/2) agonist, WIN55,212-2, and the peripherally acting CB(1)-selective agonist,
SAB-378, inhibited
pain-related responses to repetitive noxious CRD (80 mmHg) in a dose-related manner in rats. The
analgesic effects of WIN55,212-2 and
SAB-378 were blocked by the selective CB(1) antagonist
SR141716, but were not affected by the selective CB(2) antagonist
SR144528.
SR141716, per se, increased the responses to repetitive noxious CRD, indicative of
hyperalgesia, and induced
pain-related responses during non-noxious CRD (20 mmHg), indicative of
allodynia. The
cannabinoid receptor agonists anandamide,
virodhamine and
O-1602 had no effect. At
analgesic doses, WIN55,212-2 did not affect colonic compliance. In accordance to the rat data, WIN55,212-2 produced
analgesia, whereas
SR141716 induced
hyperalgesia, during noxious CRD (55 mmHg) in wild-type but not in CB(1)-knock-out mice. These data indicate that peripheral CB(1) receptors mediate the
analgesic effects of
cannabinoids on
visceral pain from the gastrointestinal tract. The allodynic and hyperalgesic responses induced by
SR141716 suggest the existence of an endogenous
cannabinoid tone and the activation of CB(1) receptors during noxious CRD.