CB₁Receptors Mediate the Analgesic Effects of Cannabinoids on Colorectal Distension-Induced Visceral Pain in Rodents

Abstract

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.

Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice

“…Cannabinoid receptors and MOR are directly involved in visceral pain, eliciting analgesic responses. 42,44 Therefore, the down-regulation of MOR and CB1 contrasts with the analgesic-like state observed, an effect likely compensated by the moderate up-regulation of CB2, which has been implicated in pain modulation in states of inflammation and immune activation. 45 Additionally, NGF has been implicated in the sensitization of visceral afferents, leading to the development of hypersensitivity.…”

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

“…Cannabinoid receptors have been implicated in pain processing in various neuropathic and inflammatory states, mainly in somatic pain [26]. Putative actions of cannabinoids on visceral sensation have been proposed, and the effects of centrally and peripherally restricted cannabinoids have been recently investigated, implicating primarily CB 1 [27][28][29] but also CB 2 [27,30]. In one interesting study, the CB 1 /CB 2 agonist WIN55,212-2 and the CB 2 agonist JWH-015 (both at doses of 10 mg/kg) attenuated the degree of visceral sensitivity under baseline conditions.…”

The Selective 5-Hydroxytryptamine 1A Antagonist, AZD7371 [3(R)-(N,N-Dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (R,R)-tartrate Monohydrate] (Robalzotan Tartrate Monohydrate), Inhibits Visceral Pain-Related Visceromotor, but Not Autonomic Cardiovascular, Responses to Colorectal Distension in Rats

“…Pseudoaffective VMRs to CRD are considered a valid surrogate maker of visceral pain in rodents and are widely used in pharmacological studies assessing the potential analgesic effects of compounds on visceral pain (Ness and Gebhart, 1988;Kä ll et al, 2007;Brusberg et al, 2008Brusberg et al, , 2009aLindström et al, 2008;Ravnefjord et al, 2008). Results obtained here show that AZD7371 dose-dependently inhibited the VMRs to CRD after systemic administration.…”

“…For the assessment of visceral pain responses, the CRD paradigm consisted of repeated phasic distensions, 12 times at 80 mm Hg, with a pulse duration of 30 s at 5-min intervals. This protocol has been used before to assess noxious responses to colorectal distension in rats (Kä ll et al, 2007;Martínez et al, 2007;Brusberg et al, 2008Brusberg et al, , 2009aLindström et al, 2008;Ravnefjord et al, 2008).…”