Effects of the peripherally acting NK₃ receptor antagonist, SB‐235375, on intestinal and somatic nociceptive responses and on intestinal motility in anaesthetized rats

Abstract

We investigated the effects of the selective NK(3) tachykinin receptor antagonist, SB-235375, on noxious signalling from gut and skin and on intestinal motility in anaesthetized rats. We also measured penetrance into brain and spinal cord. Nociceptive responses in reaction to colorectal distension and skin pinch were assessed by recording the electromyogram (EMG) from the external oblique muscle (a visceromotor response). Motility was measured by recording intraluminal pressure waves during changes in baseline pressure in the jejunum. Colorectal compliance was assessed by measuring luminal pressure change during isovolumic distension. SB-235375 (20 mg kg(-1), by i.v. bolus) reduced the EMG response to colorectal distension by over 90%. The reduction was slow at onset, peaked at about 60 min, and lasted for over 2 h. Responses to noxious skin pinch were unchanged. Amplitudes of propulsive waves in the jejunum were slightly reduced, but their frequency of occurrence was unchanged. SB-235375 decreased colorectal compliance by 5-10%. There was undetectable penetration of i.v. SB-235375 into brain or spinal cord. We conclude that SB-235375 acts peripherally to substantially reduce nociceptive signalling from colorectum without affecting noxious signalling from skin and with little effect on intestinal motility.

Functional study on TRPV1‐mediated signalling in the mouse small intestine: involvement of tachykinin receptors

“…This is in accordance with findings in the rat showing an NK 3 receptor‐mediated modulation of substance P release from spinal afferent nerve terminals 40 . In addition, there is evidence that NK 3 receptors on sensory neurons modulate the tachykininergic nociceptive response of rat spinal primary afferents 41,42 . The TRPV1 immunoreactive nerves in the mouse small intestine are also of spinal rather than vagal origin 17 …”

Effects of NMDA receptor antagonists on visceromotor reflexes and on intestinal motility, in vivo

“…Ketamine, 1.8–2.4 mg kg h −1 , in combination with α ‐chloralose, maintains anaesthesia in experiments in which visceromotor reflexes and gastrointestinal motility are measured 23 . In the present study, there was a considerable margin between the dose used for anaesthesia and the minimal doses to affect visceromotor reflexes (4 mg kg h −1 ) and motility (10–20 mg kg h −1 ).…”

“…A dose that was only two‐to‐three times the anaesthetic dose (6 mg kg h −1 ) completely blocked VMR. In the absence of blocking drugs, the EMG responses to CRD remained constant for over 5 h, 23 indicating that under the conditions of our experiments there was not sensitization of VMRs. Thus, our observations appear to contradict the idea that pain pathways that are not sensitized by inflammation or injury are not reliant on NMDA receptor mediated transmission, 4–6 although it is possible that ketamine might be acting at non‐NMDA receptor sites when it is used at greater than anaesthetic doses 29 .…”

“…Despite the observations that NMDA receptors occur in the enteric nervous system, there is almost no evidence to suggest a role for the receptors in motility reflexes. In fact, ketamine at anaesthetic doses does not appear to have effects on intestinal motility in rats 23 or pigs 24 . In human, ketamine has little effect on intestinal propulsion, as measured by gastro‐caecal transit times 25 .…”

Tachykinin Receptors as Drug Targets for Motility Disorders

“…The selective inhibition of peripheral NK 3 receptors by SB-235375 (Talnetant) reduced the nociceptive response to colorectal distension in the rat model [33,34] . The antinociceptive effects were not accompanied by any apparent alterations in motility function.…”