In vivo characterization of phencyclidine/sigma agonist-mediated inhibition of nociception.

Substance P and excitatory amino acids have been implicated as potential nociceptive neurotransmitters in several investigations. Excitatory amino acids acting at N-methyl-D-aspartate (NMDA) receptors are of particular interest because of the description of NMDA/phencyclidine (PCP) receptor complexes. PCP receptors are one of two populations of receptors resolved from a population previously referred to as 'sigma opioid' receptors. Agonists, including sigma opioid agonists, interacting with PCP receptors non-competitively inhibit NMDA-induced effects. Therefore, it has been suggested that NMDA/PCP receptor complexes in nociceptive systems may explain the antinociceptive effects of sigma opioid agonists. In the present studies, highly selective ligands for PCP and sigma receptors were coadministered with NMDA or substance P i.t. The rank order potency for inhibition of NMDA-induced behavior was (+/-)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801) greater than PCP greater than (+/-)N-allyl-normetazocine ((+/-)-SKF10,047). 1,3-Di-ortho-tolyl-guanidine (DTG) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+/-)-3PPP) were inactive. Inhibition of NMDA-induced behavior by PCP receptor agonists was not reversed by haloperidol, a putative sigma receptor antagonist. These data support PCP, but not sigma, receptor-mediated inhibition of behavior induced by NMDA. Behavior induced by i.t. administration of substance P was similarly inhibited by PCP receptor agonists, but inhibition could be reversed by coadministration of haloperidol or (+)-butaclamol. These data suggest a dopaminergic mechanism for PCP inhibition of substance P-induced behavior. Our results confirm the existence of NMDA/PCP receptor complexes in spinal systems mediating nociception and suggest agonists may induce antinociception by interacting with spinal PCP receptors.(ABSTRACT TRUNCATED AT 250 WORDS)