Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat

J.E. Haley, A.F. Sullivan, A.H. Dickenson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)218-226
Number of pages9
JournalBrain Research
Issue number1-2
Publication statusPublished - 1 Jan 1990


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