ACTIVITY AT PHENCYCLIDINE AND MU-OPIOID SITES MEDIATES THE HYPERALGESIC AND ANTINOCICEPTIVE PROPERTIES OF THE N-TERMINUS OF SUBSTANCE-P IN A MODEL OF VISCERAL PAIN

Substance P, a putative neurotransmitter or neuromodulator of nocicept ion or pain in the spinal cord, exhibits both antinociceptive and hype ralgesic properties. Investigators have shown that the N-terminal meta bolite of substance P, substance P(1-7), produces naloxone-reversible antinociception when given supraspinally and systemically in mice and hyperalgesia when injected intrathecally in rats. The goal of our inve stigation was to identify the receptors mediating these actions of sub stance P(1-7) at the initial site of release of substance P, i.e. in t he spinal cord. Thirty minutes after intrathecal injection, substance P(1-7) produced naloxone-reversible antinociception in a dose-dependen t manner in the abdominal stretch assay. When administered with naloxo ne, substance P(1-7) produced hyperalgesia 5 and 10 min after injectio n, which was inhibited by dizocilpine (MK-801), a phencyclidine ligand and non-competitive antagonist of N-methyl-D-aspartate. Antinocicepti on was inhibited by the mu-selective opioid antagonist beta-funaltrexa mine, but not by the mu(1)-selective opioid antagonist naloxonazine or the delta-selective antagonist naltrindole, indicating a mu(2)-opioid receptor-mediated effect. These findings suggest that the N-terminal portion of substance P may modulate nociception or pain, as demonstrat ed in the acetic acid abdominal stretch (writhing) assay, via activati on of two different receptor systems. Substance P(1-7)-induced hyperal gesia is mediated by a phencyclidine-sensitive mechanism and antinocic eption involves activity at mu-opioid, most likely mu(2), receptors.