COMBINED APPLICATION OF EXCITATORY AMINO-ACIDS AND SUBSTANCE-P PRODUCES LONG-LASTING CHANGES IN RESPONSES OF PRIMATE SPINOTHALAMIC TRACT NEURONS

Sensitization of dorsal horn neurons following injury may underlie the generation of secondary hyperalgesia and so the chemical basis of sen sitization is now receiving considerable attention. The present study used microiontophoretic applications of excitatory amino acids (EAA's) and substance P (SP) to test their roles in the sensitization of prim ate spinothalamic tract (STT) neurons. Of 70 STT cells examined in lam inae I-VI of the dorsal horn, 40 showed an increase in responses to on e or more EAA's following their co-application with SP. The increased responses were usually specific to either N-methyl-D-aspartate (NMDA) or to the non-NMDA agonists, quisqualate (QUIS) or pha-amino-3-hydroxy -5-methylisoxazole-4-proprionic acid (AMPA). The enhancement of EAA re sponses was long-lasting ( > 15 min) in 18 cases, was accompanied by s imilarly long-lasting increases in responses to mechanical stimulation of the receptive field in 14 cases and was accompanied by an increase in responses to either glutamate (Glu) or aspartate (Asp) in eleven c ases. A global decrease in all EAA responses tested was produced in 26 other STT neurons. The inhibition, unlike the increases, was generali zed to both NMDA and non-NMDA ligands, was long-lasting in only six ca ses and was never accompanied by a change in the responses to mechanic al stimuli. The excitatory and inhibitory effects of SP on the respons es to NMDA were uniformly reversed by the NK-1 receptor selective anta gonist, CP96345. In contrast, only the inhibitory effects of SP on the responses to QUIS or AMPA were reversed by CP96345. The long-lasting enhancement of EAA responses by SP may follow the combined synaptic re lease of the natural ligands in vivo, resulting in the sensitization o f dorsal horn neurons and secondary hyperalgesia. However, the reducti ons in EAA responses produced by SP are problematic for this hypothesi s and need further elucidation.