EVIDENCE FOR SPINAL N-METHYL-D-ASPARTATE RECEPTOR INVOLVEMENT IN PROLONGED CHEMICAL NOCICEPTION IN THE RAT

Subcutaneous injection of formalin into the hindpaw peripheral receptive field of deep dorsal horn multireceptive (convergent) nociceptive neurones was used to produce a prolonged (1 h) activation of the cells. This chemical noxious stimulus produced a first peak of firing which lasted 10 min followed by a second peak of prolonged activity which was monitored for 50 min. γ-d-glutamylglycine (DGG), a non-selective N-methyl-d-aspartate (NMDA) and quisqualate/kainate (non-NMDA) receptor antagonist was applied intrathecally both as a pretreatment and after the formalin. A complete abolition of both peaks of the formalin response was produced by DGG pretreatment (1000 μg) (n = 4). This dose produced profound inhibition of the acute C-fibre evoked responses of the same cells. However, no inhibitions were produced when the antagonist was applied once the formalin response had developed (n = 4). The selective NMDA receptor antagonist 5-amino-phosphonovaleric acid (AP5) was administered intrathecally (250 and 500 μg) as a 40 min pretreatment and caused a small inhibition of the first peak but a marked dose-related reduction in the second prolonged phase (n = 7). AP5 did not influence the C-fibre inputs onto the cells. The non-competitive NMDA receptor channel blockers, ketamine and MK801, were administered i.v. during the second phase of firing. Ketamine (1-8 mg/kg) caused a short-lasting but marked and dose-related inhibition of the neuronal responses to formalin (n = 11). MK801 (0.5-1 mg/kg) resulted in a prolonged inhibition of cell firing during the second phase of the response (n = 11). When administered intravenously as a 30 min pretreatment, MK801 (0.5-1 mg/kg) produced a dose-related inhibition of the second phase of firing with only a small inhibition of the first phase. Finally, blockade of peripheral afferent activity during the first peak by 2% lignocaine administered into the site of the formalin injection did not alter the second peak in any way (n = 10). It therefore appears that the afferent barrage produced by formalin induces NMDA mediated central activity over a relatively short time span and that once induced this activity could be one basis for changes in nociception and its modulation during longer-term pain states. © 1990.