Effect of nepadutant, a neurokinin 2 tachykinin receptor antagonist, on immediate-early gene expression after trinitrobenzenesulfonic acid-induced colitis in the rat.
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.
Birder
Lori A
LA
Department of Medicine-Laboratory of Epithelial Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. lbirder@pitt.edu
Kiss
Susanna
S
de Groat
William C
WC
Lecci
Alessandro
A
Maggi
Carlo A
CA
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000235:genetics*; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D007509:Irritants; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid
D007509:Irritants; C107754:MEN 11420; D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; D014302:Trinitrobenzenesulfonic Acid; D002211:Capsaicin