Substance P Release in the Rat Periaqueductal Gray and Preoptic Anterior Hypothalamus after Noxious Cold Stimulation: Effect of Selective Mu and Kappa Opioid Agonists1

Abstract

Intracerebral microdialysis was used to measure changes in the extracellular level of substance P (SP) released from the periaqueductal gray (PAG) and the preoptic anterior hypothalamus (POAH) of freely moving Sprague-Dawley rats after noxious cold stimulation. Artificial cerebrospinal fluid was perfused into the dialysis probe in the PAG or POAH and samples were collected every 30 min for 4 hr. SP-like immunoreactivity in the samples was measured by radioimmunoassay. In the PAG, SP base-line release was 0.43 ± 0.08 fmol/fraction. SP release was increased to 1.3 ± 0.4 fmol/fraction during the first collection period after noxious cold. Pretreatment with the selective mu opioid receptor agonist PL017 (0.8–3.4 nmol) or the kappa opioid receptor agonist dynorphin A1–17 (4.6–9.2 nmol), administered into the PAG by microinjection, produced dose-related inhibition of the cold-evoked SP release. Naloxone (10 mg/kg s.c.) administration 10 min before these opioid agonists reduced the inhibition of SP release. In the POAH, SP base-line release was 0.45 ± 0.06 fmol/fraction and noxious cold did not cause any significant change in SP release. Microdialysis of SP (271 fmol–271 pmol/μl/min, for 30 min) into the PAG, but not the POAH, induced dose-related analgesia (35–68% MPA) in the cold-water tail-flick test. However, microdialysis of SP into the POAH or PAG failed to induce any significant change in body temperature. These data suggest that 1) SP released from the PAG acts as a neuromodulator to transmit nociceptive information; 2) opioid receptor agonists can suppress this information by inhibiting SP release; 3) SP evoked by noxious cold may have a role in triggering the antinociceptive function of the PAG; and 4) SP does not appear to act as a neuromodulator for thermoregulatory responses in the POAH.