CB1 receptors mediate rimonabant-induced pruritic responses in mice: investigation of locus of action

Abstract

Rationale Cannabinoids have recently been identified as potential neuronal modulators of pruritic response, representing a potential target in the treatment of itch associated with a variety of pathophysiologic conditions. While the selective CB1 receptor antagonist rimonabant is an established pruritic agent in both animal and clinical testing, its receptor mechanism of action and anatomical loci remain unclear. Objective The purpose of this study was to determine whether CB1 receptor blockade is critical to rimonabant-induced scratching and to identify differences in scratching response based on different routes of administration. Furthermore, experiments were designed to elucidate any evidence as to whether rimonabant elicits scratching behavior through common immunologic hypersensitivity mechanisms. Results Rimonabant was equally effective at producing scratching via intraperitoneal and local subcutaneous injection. This compound also produced an intense scratching response when administered intrathecally, but had no effects after intracerebroventricular administration. Repeated administration of rimonabant led to a decreased magnitude of scratching. While rimonabant-induced scratching was not attenuated either by pretreatment with the H1 receptor antagonist loratadine or in mast cell-deficient mice, it lacked efficacy in CB1 (−/−) mice. Conclusions Rimonabant is a potent and fully effective pruritogen when administered spinally or systemically and requires CB1 receptors to induce scratching, suggesting an important spinal CB1 receptor component of action. The lack of responsiveness to H1 antagonism or mast cell deficiency supports previous findings that cannabinoids modulate itch through neuronal mechanisms, and not by traditional hypersensitivity activation.

Evaluation of sex differences in cannabinoid dependence

“…The discovery of rimonabant facilitated demonstration of dependence by producing precipitated withdrawal (Tsou et al, 1995; Cook et al, 1998); however, rimonabant produces effects when given alone, including pruritis (present study; Schlosburg et al, 2011), increased locomotion (Bass et al, 2002), and appetite suppression (Thornton-Jones et al, 2006). Somatic signs of precipitated withdrawal in the THC-treated rats were also observed, including paw tremors and head twitches.…”

“…All injections were given subcutaneously (s.c.) except the second injection on day 7, which was given intraperitoneally (i.p.). The chronic dosing regimen, including route of administration, was based upon procedures established in numerous previous studies of cannabinoid tolerance and dependence in rodents (Beardsley and Martin, 2000; Falenski et al, 2010; Schlosburg et al, 2011; Wiley et al, 2007). Vaginal smears were collected once daily from female rats beginning 7 days prior to the start of drug administration, and ending 8 days after the last day of drug administration (22 days total).…”

Analysis of Tolerance and Behavioral/Physical Dependence during Chronic CB1Agonist Treatment: Effects of CB1Agonists, Antagonists, and Noncannabinoid Drugs

“…Such effects on overt behavior may be species dependent or context dependent; nonetheless, doses of rimonabant that disrupted operant behavior in AM411-treated squirrel monkeys did not reveal easily identifiable or consistent effects on overt behavior aside from profuse salivation. However, profuse salivation can be observed following the repeated administration of rimonabant itself and, thus, cannot be viewed as a sufficient indicator of physical dependence (unpublished observations; including rimonabant-induced scratching in nondependent rats/mice) (Janoyan et al, 2002;Jarbe et al, 2006;Schlosburg et al, 2011). Taken together, the above findings suggest that the term behavioral dependence-which, beyond displacement of the agonist from its binding site, does not presume alterations in substrate that mediate physical dependence -still may be the most appropriate term to describe changes in operant behavior that are precipitated by an antagonist either during chronic CB 1 agonist treatment or after its discontinuation.…”

Oleoylethanolamide: A Novel Potential Pharmacological Alternative to Cannabinoid Antagonists for the Control of Appetite

“…In particular several studies described a syndrome of compulsive scratching and grooming in rodents as well as severe itching and scratching in humans [14, 67, 68]. Initially such effects were considered to be responsible for the anorexiant actions of the drugs, due to a sort of response competition between eating and grooming/scratching behaviors.…”