TRIFLUOPERAZINE MODULATES [H-3] RESINIFERATOXIN BINDING BY HUMAN AND RAT VANILLOID (CAPSAICIN) RECEPTORS AND AFFECTS CA-45 UPTAKE BY ADULT-RAT DORSAL-ROOT GANGLION NEURONS

Optimum treatment of neuropathic pain includes the use of adjuvant ana lgesics such as antipsychotic drugs and tricyclic antidepressants. Alt hough the mechanism of their analgesic action is not known, it is poss ible that such agents act directly on pain pathways. The ability of ca psaicin and its analogs to selectively deactivate primary afferent neu rons provides a basis for their use in human therapy to relieve a numb er of chronic pain conditions. We examined whether the phenothiazine a ntipsychotic drug trifluoperazine (TFP) as well as other neuroleptics and tricyclic antidepressants have an effect on the agonist binding pr operties and the activation of the human and rat vanilloid receptors. Binding of [H-3]resiniferatoxin (RTX) to membrane preparations of huma n dorsal horn and rat whole spinal cord was affected by TFP in a bipha sic fashion, with an initial 25 and 65% enhancement of [H-3]RTX bindin g, respectively, preceding inhibition. The apparent K-i values for inh ibition were 3.93 +/- 0.13 mu M for human dorsal horn and 7.91 +/- 0.6 2 mu M for rat spinal cord. Scatchard analyses revealed that TFP affec ted both the affinity and the cooperativity of [H-3]RTX binding by the receptors, leaving the receptor density unaltered. Similar effects on [H-3]RTX binding to rat spinal cord membranes were also induced by ot her antipsychotic phenothiazines and other types of antipsychotics, by phenothiazines without antipsychotic actions, as well as by tricyclic antidepressants. In cultures of dorsal root ganglion neurones, TFP at concentrations that increased [H-3]RTX binding (1-3 mu M) also induce d an increase in Ca-45 uptake; this increase was absent in cultures pr epared from capsaicin desensitized animals. Furthermore, TFP at a conc entration of 10 mu M also increased the extent of Ca-45 uptake induced by 0.3 mu M capsaicin. Our results suggest that at therapeutic concen trations (0.5-5.0 mu M) TFP may increase the affinity of the vanilloid receptor for agonists and thereby accelerate its desensitization.