In vivo characterization of phencyclidine/σ 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 ‘σ opioid’ receptors. Agonists, including σ 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 σ opioid agonists. In the present studies, highly selective ligands for PCP and σ receptors were coadministered with NMDA or substance P i.t. The rank order potency for inhibition of NMDA-induced behavior was (±)-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10 -imine maleate (MK-801) > PCP > (±)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 σ receptor antagonist. These data support PCP, but not σ, 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. In spite of many similarities between substance P- and NMDA-induced nociception, PCP agonist-mediated inhibition of substance P appears to involve indirect activation of spinal dopaminergic systems, rather than the direct interactions with PCP receptors observed with NMDA-induced nociception.