Gender‐related differential effect of tachykinin NK₂ receptor‐mediated visceral hyperalgesia in guinea pig colon

Abstract

BACKGROUND AND PURPOSE The tachykinin NK 2 receptor antagonist ibodutant is under Phase III clinical investigation to treat female patients with irritable bowel syndrome. The aim of this study was to investigate the NK 2 receptor-related gender specificity in a model of colitis. EXPERIMENTAL APPROACH Colitis was induced by rectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS, 0.5 mL, 30 mg·mL À1 in 30% ethanol) in female and male guinea pigs. Electromyographic recording of the responses to colorectal distension (CRD) was made 3 days later. Ibodutant (0.33 , 0.65, 1.9 and 6.5 mg·kg À1) was given s.c., 30 min before CRD. Release of neurokinin A and substance P from isolated mucosal and smooth muscle tissues following treatment with KCl (80 mM) or capsaicin (10 μM) was measured by EIA. Plasma pharmacokinetics of ibodutant following a single s.c. administration (0.73 or 2.1 mg·kg À1) were measured over 24 h. KEY RESULTS Ibodutant did not affect abdominal contractions in control animals. After TNBS-induced colitis, ibodutant prevented the increased visceral hypersensitivity to CRD in females, at lower doses than in males. Ibodutant pharmacokinetics did not differ between females and males. Tachykinins release was greater in smooth muscle than in mucosal samples. Capsaicin-stimulated release of tachykinins from inflamed mucosal samples from females was significantly lower than in males. CONCLUSIONS AND IMPLICATIONS Ibodutant prevented abdominal nociception in a model of visceral hypersensitivity in guinea pigs with a greater efficacy in females than in males. Our results highlight a gender-related difference in colonic visceral hypersensitivity and mucosal nerve activation. Abbreviations IBS, irritable bowel syndrome

Experimental Models of Irritable Bowel Syndrome and the Role of the Enteric Neurotransmission

“…NK2r antagonists have been proven effective in animal models of visceral hyperalgesia induced by inflammation [ 57 , 58 ] or WAS [ 59 ]. Nepadutant [ 58 ], ibodutant [ 57 ] or saredutant [ 59 ] were found able to inhibit rectal hypersensitive responses in rats, guinea-pigs or gerbils pretreated with Trinitrobenzenesulfonic acid (TNBS) or previously subjected to restraint, suggesting that the NK2r has a role in mediating visceral allodynia/hyperalgesia.…”

“…NK2r antagonists have been proven effective in animal models of visceral hyperalgesia induced by inflammation [ 57 , 58 ] or WAS [ 59 ]. Nepadutant [ 58 ], ibodutant [ 57 ] or saredutant [ 59 ] were found able to inhibit rectal hypersensitive responses in rats, guinea-pigs or gerbils pretreated with Trinitrobenzenesulfonic acid (TNBS) or previously subjected to restraint, suggesting that the NK2r has a role in mediating visceral allodynia/hyperalgesia. This role was further supported by the studies of Birder et al [ 60 ], who showed that the increased expression of either c-fos and c-jun proto-oncogene markers in spinal cord and dorsal root ganglia neurons of rats pretreated with TNBS was prevented by nepadutant, and by Laird et al [ 61 ], who found nepadutant capable of preventing the hypersensitivity of single spinal cord neurons responding to colorectal distension or pelvic nerve stimulation in rats pretreated with intracolonic acetic acid.…”

“…Also, the NK3r (located at peripheral or/and central level) could play a role in visceral hyperalgesia, due to the reported effectiveness of either intraperitoneal [ 64 ] or intrathecal [ 65 ] administration of the NK3r selective antagonist SR 142801 in reducing reflex abdominal contractions elicited by various nociceptive stimuli. Gender and species differences are reported in the modulating effect on pain of tachykinin antagonists [ 57 , 66 , 67 ].…”

Direct activation of tachykinin receptors within baroreflex afferent pathway and neurocontrol of blood pressure regulation

“…Early study has shown that SP can be synthesized within the NG and bidirectionally transported toward the CNS and thoracic and abdominal viscera . Gender difference regarding SP released from primary afferents evoked by formalin has been reported recently . However, the resting level of SP in NG tissue and estrogen sensitivity have not been evaluated.…”

“…29 Gender difference regarding SP released from primary afferents evoked by formalin has been reported recently. 30,31 However, the resting level of SP in NG tissue and estrogen sensitivity have not been evaluated. In this regard, ELISA assay was performed and the result showed no difference in serum level SP ( Figure S1) among adult male, age-matched female, and OVX female rats.…”