of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium. Am J Physiol Gastrointest Liver Physiol 291: G364 -G371, 2006. First published March 30, 2006 doi:10.1152/ajpgi.00407.2005.-Oil of mustard (OM) is a potent neuronal activator that is known to elicit visceral hyperalgesia when given intracolonically, but the full extent to which OM is also proinflammatory in the gastrointestinal tract is not known. We have previously shown that male CD-1 mice given a single administration of 0.5% OM develop a severe colitis that is maximum at day 3 and that gradually lessens until essentially absent by day 14. OM-induced neuronal stimulation is reported to be reduced by cannabinoid agonists, and cannabinoid receptor 1 (CB1R) Ϫ/Ϫ mice have exacerbated experimental colitis. Therefore, we examined the role of cannabinoids in this OM-induced 3-day model of colitis in CD-1 mice and in a 7-day dextran sulfate sodium (DSS) colitis model in BALB/c mice. In OM colitis, the CB1R-selective agonist ACEA and the CB2R-selective agonist JWH-133 reduced (P Ͻ 0.05) colon weight gain (means Ϯ SE; 82 Ϯ 13% and 47 Ϯ 15% inhibition, respectively), colon shrinkage (98 Ϯ 24% and 42 Ϯ 12%, respectively), colon inflammatory damage score (49 Ϯ 11% and 40 Ϯ 12%, respectively), and diarrhea (58 Ϯ 12% and 43 Ϯ 11%, respectively). Histological damage was similarly reduced by these treatments. Likewise, CBR agonists attenuated DSS colitis, albeit at higher doses; ACEA at 10 mg/kg, twice daily, inhibited (P Ͻ 0.05) macroscopic and microscopic scores (46 Ϯ 9% and 63 Ϯ 7%, respectively); whereas 20 mg/kg, twice daily, of JWH-133 was required to diminish (P Ͻ 0.05) macroscopic and microscopic scores (29 Ϯ 7% and 43 Ϯ 5%, respectively). CB1R and CB2R immunostaining of colon sections revealed that CB1R in enteric neurons was more intense in colitic vs. control mice; however, CB1R was also increased in the endothelial layer in OM colitis only. CB2R immunostaining was more marked in infiltrated immune cells in OM colitis. These findings validate the OM colitis model with respect to the DSS model and provide strong support to the emerging idea that cannabinoid receptor activation mediates protective mechanisms in experimental colitis. The demonstration of CB1R agonist effects in colitis support the neurogenic nature of the OM-induced colitis model and reinforce the importance of neuronal activation in intestinal inflammation.
Neurogenic mechanisms have been implicated in the induction of inflammatory bowel disease (IBD). Vanilloid receptor type 1 (TRPV1) has been visualized on nerve terminals of intrinsic and extrinsic afferent neurones innervating the gastrointestinal tract and local administration of a TRPV1 antagonist, capsazepine, reduces the severity of dextran sulphate sodium (DSS)-induced colitis in rats (Gut 2003; 52: 713-9(1)). Our aim was to test whether systemically or orally administered TRPV1 antagonists attenuate experimental colitis induced by 5% DSS in Balb/c mice. Intraperitoneal capsazepine (2.5 mg kg(-1), bid), significantly reduced the overall macroscopic damage severity compared with vehicle-treated animals (80% inhibition, P < 0.05); however, there was no effect on myeloperoxidase (MPO) levels. An experimental TRPV1 antagonist given orally was tested against DSS-induced colitis, and shown to reverse the macroscopic damage score at doses of 0.5 and 5.0 mg kg(-1). Epithelial damage assessed microscopically was significantly reduced. MPO levels were attenuated by approximately 50%, and diarrhoea scores were reduced by as much as 70%. These results suggest that pharmacological modulation of TRPV1 attenuates indices of experimental colitis in mice, and that development of orally active TRPV1 antagonists might have therapeutic potential for the treatment of IBD.
Oil of mustard (OM), administered intracolonically, produces severe colitis in mice that is maximized within 3 days. The purpose of this study was to characterize the cytokine response, and to establish expression patterns of enteric neuronal mediators and neuronal receptors affected during active colitis. We measured the changes in the mRNA levels for neuronal receptors and mediators by real-time PCR, and cytokine and chemokine protein levels in the affected tissue. Significant increases in neuronal receptors, such as transient receptor potential A1 (TRPA1), cannabinoid type 1 receptor, neurokinin 1 receptor (NK1R) and delta-opioid receptor; prokineticin-1 receptor; and soluble mediators, such as prodynorphin, proenkephalin1, NK1, prokineticin-1 and secretory leukocyte protease inhibitor, occurred. Significant increases in cytokines, such as interleukin (IL)-1beta, IL-6 and granulocyte macrophage colony stimulating factor (GM-CSF), and in chemokines, such as macrophage chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 (MIP-1alpha) and Kupffer cell derived chemokine (KC), were detected, with no changes in T-cell-derived cytokines. Furthermore, immunodeficient C57Bl/6 RAG2(-/-) mice exhibited OM colitis of equal severity as seen in wt C57Bl/6 and CD-1 mice. The results demonstrate rapidly increased levels of mRNA for neuronal receptors and soluble mediators associated with pain and inflammation, and increases in cytokines associated with macrophage and neutrophil activation and recruitment. Collectively, the data support a neurogenic component in OM colitis coupled with a myeloid cell-related, T- and B-cell-independent inflammatory component.
The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.
Cannabinoids are known to be clinically beneficial for control of appetite disorders and nausea/vomiting, with emerging data that they can impact other GI disorders, such as inflammation. Post-inflammatory irritable bowel syndrome (PI-IBS) is a condition of perturbed intestinal function that occurs subsequent to earlier periods of intestinal inflammation. Cannabinoid 1 receptor (CB1R) and CB2R alterations in GI inflammation have been demonstrated in both animal models and clinically, but their continuing role in the post-inflammatory period has only been implicated to date. Therefore, to provide direct evidence for CBR involvement in altered GI functions in the absence of overt inflammation, we used a model of enhanced upper GI transit that persists for up to 4 weeks after a single insult by intracolonic 0.5% oil of mustard (OM) in mice. In mice administered OM, CB1R immunostaining in the myenteric plexus was reduced at day 7, when colonic inflammation is subsiding, and then increased at 28 days, compared to tissue from age-matched vehicle-treated mice. In the lamina propria CB2R immunostaining density was also increased at day 28. In mice tested 28 day after OM, either a CB1R-selective agonist, ACEA (1 and 3 mg/kg, s.c.) or a CB2R-selective agonist, JWH-133 (3 and 10 mg/kg, s.c.) reduced the enhanced small intestinal transit in a dose-related manner. Doses of ACEA and JWH-133 (1 mg/kg), alone or combined, reduced small intestinal transit of OM-treated mice to a greater extent than control mice. Thus, in this post-colonic inflammation model, both CBR subtypes are up-regulated and there is increased efficacy of both CB1R and CB2R agonists. We conclude that CBR remodeling occurs not only during GI inflammation but continues during the recovery phase. Thus, either CB1R- or CB2-selective agonists could be efficacious for modulating GI motility in individuals experiencing diarrhea-predominant PI-IBS.
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