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 nociception or pain in the spinal cord, exhibits both antinociceptive and hyperalgesic properties. Investigators have shown that the N-terminal metabolite 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 investigation was to identify the receptors mediating these actions of substance P(1-7) at the initial site of release of substance P i.e. in the spinal cord. Thirty minutes after intrathecal injection, substance P(1-7) produced naloxone-reversible antinociception in a dose-dependent manner in the abdominal stretch assay. When administered with naloxone, substance P(1-7) produced hyperalgesia 5 and 10 min after injection, which was inhibited by dizocilpine (MK-801), a phencyclidine ligand and non-competitive antagonist of N-methyl-d-aspartate. Antinociception was inhibited by the μ-selective opioid antagonist β-funaltrexamine, but not by the μ-selective opioid antagonist naloxonazine or the δ-selective antagonist naltrindole, indicating a μ₂-opioid receptor-mediated effect. These findings suggest that the N-terminal portion of substance P may modulate nociception or pain, as demonstrated in the acetic acid abdominal stretch (writhing) assay, via activation of two different receptor systems. Substance P(1-7)-induced hyperalgesia is mediated by a phencyclidine-sensitive mechanism and antinociception involves activity at μ-opioid, most likely μ₂, receptors.