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

Abstract

Antagonists of NMDA receptors can inhibit both the transmission of pain signals from the intestine and enteric reflexes. However, it is unknown whether doses of the NMDA antagonist, ketamine, that are used in anaesthetic mixtures suppress motility reflexes and visceromotor responses (VMRs). In fact, whether intestinal motility is affected by NMDA receptor blockers in vivo has been little investigated. We studied the effects of ketamine and memantine, administered intravenously or intrathecally. Rats were maintained under alpha-chloralose plus xylazine or pentobarbitone anaesthesia; VMR and jejunal motility were measured. Under alpha-chloralose/xylazine anaesthesia, i.v. ketamine inhibited VMRs at 6 mg kg h(-1), but not at 3 mg kg h(-1). It did not inhibit propulsive reflexes in the jejunum at 10 mg kg h(-1), but reduced them by 30% at 20 mg kg h(-1). Under alpha-chloralose/pentobarbitone anaesthesia, i.v. ketamine reduced propulsive reflexes at 40 mg kg h(-1) and VMR at 10 mg kg h(-1). Memantine inhibited VMRs at 20 mg kg h(-1) and propulsion at 2 mg kg h(-1). Ketamine and memantine, intrathecally, prevented VMRs, but not jejunal propulsion. We conclude that peripherally administered ketamine reduces both VMR and motility reflexes, but not at doses used in anaesthetic mixes (1.8-2.4 mg kg h(-1)). Effects on motility reflexes are likely to be due to non-NMDA receptor actions, possibly on nicotinic receptors.

Systemic Effects of a Prolonged Continuous Infusion of Ketamine in Healthy Horses

“…Subanesthetic doses of ketamine as CRI decreased the amplitude of duodenal contractions in horses a . This is in contrast to studies in other species in which low doses of ketamine did not affect intestinal motility 8,9 . In addition to its analgesic properties, ketamine has well‐documented anti‐inflammatory properties in several species.…”

“…In addition, ketamine can have a direct inhibitory effect on gastrointestinal motility through antagonism of γ‐aminobutyric acid receptors in the enteric nervous system leading to decreased release of acetylcholine 18 . Low doses of ketamine to rats, dogs, and humans did not significantly affect gastrointestinal motility 8,9,19 . A single low dose of ketamine decreased duodenal migrating motor complex phase II (irregular muscle contractions) duration and prolonged phase I (period of quiescence) in pigs 20 .…”

“…18 Low doses of ketamine to rats, dogs, and humans did not significantly affect gastrointestinal motility. 8,9,19 A single low dose of ketamine decreased duodenal migrating motor complex phase II (irregular muscle contractions) duration and prolonged phase I (period of quiescence) in pigs. 20 The current study evaluated total gastrointestinal transit time; therefore it is not possible to determine which segment(s) of the gastrointestinal tract contributed to the decrease in overall motility or the mechanism by which the decrease in transit time occurred.…”

“…a This is in contrast to studies in other species in which low doses of ketamine did not affect intestinal motility. 8,9 In addition to its analgesic properties, ketamine has well-documented antiinflammatory properties in several species. Ketamine reduces the production of TNF-a, IL-6, and IL-8 in humans, dogs, and rats in response to endotoxin stimulation.…”

Corticotropin-releasing factor type 1 receptors mediate the visceral hyperalgesia induced by repeated psychological stress in rats

“…The involvement of CRF 1 in the maintenance of chronic stress-induced visceral hyperalgesia is supported by our observation that acute treatment with CP-154,526 normalized the VMR to CRD at a pressure of 40 mmHg (but not 60 mmHg), both these pressures being over the pain threshold level in healthy human subjects and rats (10,55). In previous studies with the use of a single stress session, we found that the same dose of CP-154,526 normalized stress-induced visceral hyperalgesia at distention pressures of both 40 and 60 mmHg (2,40,52,53).…”