Effects of the capsaicin analogue resiniferatoxin on spinal nociceptive mechanisms in the rat: behavioral, electrophysiological and in situ hybridization studies.
The effect of a single subcutaneous (s.c.) injection of the ultrapotent capsaicin analogue resiniferatoxin (RTX) on responses of adult rats to noxious thermal and mechanical stimulation was examined. The effects of RTX treatment on the nociceptive flexor reflex and activity-dependent increase in spinal excitability after conditioning C-fiber stimulation (CS) were also assessed. Finally, the expression of galanin message associated peptide (GMAP) mRNA in dorsal root ganglion (DRG) cells and the effects of the high affinity galanin receptor antagonist M35 on the flexor reflex in RTX-treated rats were evaluated. RTX, but not vehicle, produced marked thermal hypoalgesia on the hot plate test with partial recovery in about 50% of animals after about 2 weeks and no recovery in the remaining rats after 4 weeks. In all animals there was only a transient and moderate increase in paw withdrawal threshold to mechanical pressure. The flexor reflex in response to a C-fiber CS train was recorded 15-35 days after RTX or vehicle treatment. There was no difference between RTX and vehicle treated rats on baseline response, but RTX treatment lead to less wind-up during the CS and reduced hyperexcitability. This was particularly the case for rats which did not recover from RTX-induced hypoalgesia. The C-fiber mediated hyperexcitability was potentiated by the galanin receptor antagonist M35, more so in the non-recovered rats than in the partially recovered rats. The number of DRG cells expressing GMAP mRNA was significantly higher in non-recovered than in partially recovered rats. Thus, RTX produced marked and prolonged impairment of capsaicin-sensitive afferents and upregulation of the inhibitory neuropeptides GMAP and galanin in DRG neurons, which may underlie the prolonged effect of RTX.