INHIBITION OF PRIMATE SPINOTHALAMIC TRACT NEURONS BY SPINAL GLYCINE AND GABA IS REDUCED DURING CENTRAL SENSITIZATION

1. In our previous work, we demonstrated that the glycinergic and GABA ergic mechanisms that help mediate the descending inhibition from the periaqueductal gray exert a tonic modulation of nociceptive inputs thr ough spinal glycine and gamma-aminobutyric acid (GABA) receptors. This study was designed to examine further possible changes in the inhibit ion of the activity of spinothalamic tract (STT) neurons mediated by s pinal glycine and GABA receptors when STT cells are sensitized by intr adermal injection of capsaicin, and to investigate the role of the pro tein kinase C (PKC) system in the functional modulation of these recep tors. 2. Although the responses of STT cells to cutaneous mechanical s timuli were sensitized by intradermal injection of capsaicin, the inhi bition of the responses of all STT cells tested to noxious cutaneous s timuli produced by iontophoretic release of glycine and GABA was signi ficantly attenuated. The inhibition elicited by iontophoretic applicat ion of a GABA(A) agonist, muscimol, was reduced in some of the cells t ested. 3. When the spinal cord dorsal horn was pretreated with a selec tive tive PKC inhibitor, -([1-oxotridecyl-2-piperidinyl]-methyl)hexana mide, by microdialysis, sensitization of STT cells by capsaicin inject ion and the accompanying attenuation of glycine- and GABA-induced inhi bition were prevented. 4. Sensitization of STT cells to cutaneous mech anical stimuli was also induced by administration of the PKC activator , 12-O-tetradecanoylphorbol-13-acetate, into the spinal dorsal horn. T he inhibition produced by iontophoretic release of glycine, GABA, and muscimol was found to be reduced in most cells examined when this phor bol ester was used. An inactive phorbol ester, 4 alpha-phorbol 12,13-d idecanoate, did not produce significant effects on cellular activity. 5. These results suggest that there is an activation of PKC in the spi nal cord when STT neurons are sensitized after intradermal injection o f capsaicin or administration of phorbol ester. This sensitization is likely to be involved in the development of allodynia and secondary hy peralgesia not only by enhancing the responses of excitatory amino aci d receptors but also by desensitizing glycine and GABA receptors.