Stimulation of the periaqueductal gray subdues sensitized pain in morphine- and meperidine-dependent rats.

Because increased tolerance of narcotics is marked by progressive deactivation of the descending antinociceptive system, a question was raised whether stimulation of the periaqueductal gray matter (PAG) would have any electroanalgetic effect in animals adapted to increasing doses of narcotics. The daily dose of morphine (10 mg/kg) administered to rats was increased on alternate days by 10 mg/kg to 100 mg/kg/day. To another group, the daily dose of meperidine was increased from 15 mg/kg by 15 mg/kg to 150 mg/kg/day. Electrophysiological experiments were conducted under chloralose and urethane anesthesia 16 h after the last injection of morphine or meperidine. Spike potentials evoked from individual neurons of the nucleus ventralis posterolateralis by single-pulse stimulation of the sciatic nerve were accumulated in poststimulus time histograms. For nociceptive neurons the histograms were characterized by a short-latency activity peak and at least two late (270 and 420 ms) peaks. For non-nociceptive neurons the histograms had no late activity peaks. In control rats, stimulation of the PAG (400 ms at 70/s) prior to each sciatic nerve pulse reorganized the late activity peaks of the nociceptive neurons: a single late peak occurred during the 280 to 400 ms poststimulus interval, indicating suppression of pain by electroanalgesia. In rats adapted to morphine or meperidine, intracarotid infusion of naloxone lowered the nociceptive threshold. Stimulation of the PAG reorganized the late peaks but only if the sciatic nerve stimulation was not increased. At the voltage used to stimulate the sciatic nerve in control animals, two separate late peaks appeared, which were subdued by PAG stimulation after intracarotid infusion of 5-hydroxytryptophan (5-HTP). These results affirmed previous findings that electroanalgesia is induced by activity in an ascending and a descending pathway, both originating from the PAG. Since the function of the descending pathway is impaired by repeated administration of narcotics, only the pathway ascending to the somesthetic thalamus can be activated to mask pain, unless 5-HTP is injected. The latter renews the functional capacity of the descending pathway and thus reinstates the full capacity of electroanalgesia.