men-11420 and Colitis

Tachykinins have been implicated in inflammatory responses such as those occurring in inflammatory bowel disease. Accordingly, we investigated the effect of a selective neurokinin (NK) 2 receptor antagonist, nepadutant, on proto-oncogene expression in the L(6)-S(1) spinal cord as well as in dorsal root ganglion (DRG) neurons after either non-noxious colorectal distension (CRD) or trinitrobenzenesulfonic acid (TNBS)-induced colitis in the adult rat. In both preparations, c-fos was expressed in similar spinal cord regions, including medial and lateral dorsal horn, dorsal commissure (DCM; laminae X above the central canal), and the sacral parasympathetic nucleus (SPN, laminae V-VII). However, TNBS-induced colitis produced significantly larger numbers (8-10-fold increase over control) of Fos-positive spinal cord neurons. In addition, there was also a significant increase (3-4-fold) in the number of Jun-positive colon DRG neurons after colitis compared with CRD. Nepadutant had no significant effect on proto-oncogene expression induced by CRD in either spinal cord neurons or DRG neurons. In contrast, nepadutant significantly decreased (70%) the number of Fos-positive neurons in dorsal horn, DCM, and SPN spinal cord regions and significantly decreased (75%) the number of Jun-positive DRG neurons after TNBS-induced irritation of the colon. These findings indicate that nepadutant suppresses the responses of colonic afferent neurons to nociceptive stimuli and that NK2 receptor antagonists may be beneficial in the treatment of sensory symptoms of colitis.

Topics: Animals; Capsaicin; Colitis; Female; Ganglia, Spinal; Gene Expression; Genes, fos; Genes, Immediate-Early; Genes, jun; Irritants; Neurons; Peptides, Cyclic; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-2; Spinal Cord; Trinitrobenzenesulfonic Acid

Tachykinin NK2 receptors are implicated in nociception and the control of intestinal motility. Here we examined their involvement in responses of spinal lumbosacral neurons with colon input to distension of normal or inflamed colon in anesthetized rats. The responses of single neurons to colorectal distension (5-80 mmHg), to electrical stimulation of the pelvic nerve (bypassing sensory receptors) and to somatic stimulation were characterized. The effect of cumulative doses of an NK2 receptor antagonist, MEN 11420 (10-1000 microg kg(-1) IV), on responses to these stimuli was tested in control conditions (n=6), or 45 min after intracolonic instillation of acetic acid (n=6). After colonic inflammation, neuronal responses to colorectal distension and pelvic nerve stimulation were significantly greater. MEN 11420 dose-dependently inhibited the enhanced responses to colorectal distension after inflammation (ID50=402+/-14 microg kg(-1)), but had no significant effect on responses to pelvic nerve stimulation or distension of the normal colon, suggesting a peripheral action selective for the inflamed colon. We conclude that MEN 11420 possesses peripheral anti-hyperalgesic effects on neuronal responses to colorectal distension. These results provide a neurophysiological basis for a possible use of tachykinin NK2 receptor antagonists in treating abdominal pain in irritable bowel syndrome patients.

Topics: Animals; Colitis; Dose-Response Relationship, Drug; Electric Stimulation; Female; Neurons; Peptides, Cyclic; Posterior Horn Cells; Rats; Rats, Wistar; Receptors, Neurokinin-2; Spinal Cord