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. gamma-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 micrograms) (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 micrograms) 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).(ABSTRACT TRUNCATED AT 250 WORDS)
Haley
J E
JE
Department of Pharmacology, University College London, U.K.
Sullivan
A F
AF
Dickenson
A H
AH
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology*; D000818:Animals; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D016291:Dizocilpine Maleate; D004558:Electric Stimulation; D005557:Formaldehyde; D007649:Ketamine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology; D010146:Pain / Q000503:physiopathology*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*
D003986:Dibenzocycloheptenes; D004151:Dipeptides; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C028929:gamma-glutamylglycine; D005557:Formaldehyde; D007649:Ketamine; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate