Differential effects of N -Methyl-D-aspartate receptor blockade on nociceptive somatic and visceral reflexes

Abstract

N-methyl-D-aspartate (NMDA) receptors appear to play little part in nociceptive responses evoked by acute stimulation of normal somatic tissues, but rather are involved in hyperalgesic responses after peripheral injury and inflammation. Previous studies from this laboratory have shown important differences in the neural organization of somatic and visceral nociceptive pathways. Here, we have explored the role of NMDA receptors in processing acute visceral noxious input, compared with somatic noxious input. The left ureter was cannulated close to the bladder in adult female Wistar rats anaesthetized with pentobarbitone (50 mg/kg i.p). Graded distentions of the ureter (30 s, 25-80 mmHg) evoked increases in blood pressure. These responses were dose-dependently inhibited by the NMDA receptor ion channel blockers ketamine and memantine (ID50 = 2.4+/-1.6 and 14.5+/-1.3 mg/kg, i.v.), and by the Merz glycine site antagonist Mrz 2/ 576 (ID50 = 0.2+/-0.2 mg/kg). Graded pinch stimuli (30 s, 2-4 N) of one hind-paw evoked similar pressor responses which were not affected by ketamine (up to 10 mg/kg). Similarly, Mrz 2/576 did not affect responses to noxious pinch, whereas memantine (ID50 = 17+/-12 mg/kg) did inhibit responses to pinch stimuli. However, in the dose range used neither ketamine nor Mrz 2/576 inhibited a pressor response of non-nociceptive origin (produced by bilateral carotid occlusion) whereas memantine did. Thus the effects of memantine are likely due to a non-specific cardiovascular effect. These results show that NMDA receptor antagonists inhibit nociceptive reflexes evoked from the normal ureter, and suggest that NMDA receptors are involved in the processing of acute nociceptive inputs from viscera. We conclude that acute stimulation of normal visceral tissue provokes intense responses that recruit neural mechanisms mediated by NMDA receptors. However, in somatic pathways, these mechanisms are recruited only by an enhanced peripheral input such as that produced after injury or inflammation.

Effects of Tachykinin NK1 Receptor Antagonists on the Viscerosensory Response Caused by Colorectal Distention in Rabbits

“…These findings are in agreement with those of previous studies (Poynard et al, 1994;Maxton et al, 1996). Other candidate receptors known to be associated with visceral pain are tachykinin NK 2 , calcitonin gene-related peptide, and N-methyl-D-aspartate receptors (McLean et al, 1997;Plourde et al, 1997;Olivar and Laird, 1999); however, further studies will be required to clarify the involvement of these receptors in the viscerosensory responses caused by colorectal distention in rabbits.…”

Is it All about Sex? Acupuncture for the Treatment of Pain from a Biological and Gender Perspective

“…46;55-56 Visceral nociceptive responses have greater sensitivity to peripherally administered NMDAR antagonists than those arising from somatic tissues implying a greater role of these NMDARs in visceral pain transmission. [57][58] In peripheral tissue, stimulation of NMDARs causes release of the neuropeptides like substance P (SP) and calcitonin gene-related peptide (CGRP) from capsaicin-sensitive peripheral nerve terminals. 57 These neuropeptides and growth factors contribute to neurogenic inflammation.…”

EphrinB2 induces pelvic-urethra reflex potentiation via Src kinase-dependent tyrosine phosphorylation of NR2B

“…Spinal administration of NMDAR agonists has dose-dependently facilitated the visceromotor reflex, together with pressor responses to pelvic noxious stimulation (14). Conversely, blockage of NMDAR using pharmacological antagonists has inhibited pain behavior caused by irritation of the pelvic viscera (24,43). Among subunits of NMDAR, the role of the NR2B subunit in pain development has been intensively investigated, as electrophysiological studies have demonstrated that phosphorylation of specific NR2B tyrosine residues is an important determinant for NMDAR-mediated currents (22), which defines the role of NMDARs in pain-related neural plasticity (3,17,18,20).…”