It has been previously established that a bulbar relay plays an important role in descending inhibition of spinal dorsal horn nociceptive neurons and nociceptive reflexes produced by stimulation in the midbrain periaqueductal gray (PAG). In the present study, selected receptor antagonists were microinjected into the medial medullary nucleus raphe magnus (NRM) to determine whether descending inhibition of the tail flick (TF) reflex in the rat produced by focal electrical stimulation in the midbrain PAG was mediated by serotonin, opioid, or glutamate receptors on bulbospinal neurons in the NRM. It was determined in initial experiments that the serotonin receptor antagonist methysergide, the opioid receptor antagonist naloxone, the local anesthetic lidocaine, and the glutamate receptor antagonists gamma-D-glutamylglycine (DGG) and DL-2-amino-5-phosphonovalerate (APV) microinjected into the medulla all significantly increased the threshold of focal electrical stimulation in the medulla required to inhibit the TF reflex. The antinociceptive efficacy of agonists at opioid, serotonin, and glutamate receptors was also tested in other experiments. The microinjection of morphine (2.5-10 micrograms) into the NRM increased significantly TF latencies in a dose-dependent manner in rats in the awake or lightly anesthetized state; morphine was more potent in awake rats. Inhibition of the TF reflex produced by the microinjection of morphine was reversed by a subsequent microinjection of naloxone into the same site in the medulla. The microinjection of serotonin (5 and 10 micrograms), however, did not affect the latency of the TF reflex in either awake or lightly anesthetized rats. Glutamate (100 microM, 0.5 microliter) microinjected into the rostral ventral medulla produced an inhibition of the TF reflex of short duration that could be blocked or attenuated significantly by the glutamate receptor antagonists DGG or APV microinjected into the same site. In subsequent experiments, a nonspecific functional block was introduced adjacent to the NRM bilaterally in the medullary reticular formations (MRFs) by the microinjection of the local anesthetic lidocaine; receptor antagonists were then microinjected into the NRM and their effect on the threshold of focal electrical stimulation in the PAG to inhibit the TF reflex determined. No increase was seen in stimulation thresholds in the PAG following the microinjection of either methysergide or naloxone into the NRM. Following the microinjection of lidocaine, DGG or APV into the NRM, the stimulation threshold in the PAG for inhibition of the TF reflex was increased significantly.(ABSTRACT TRUNCATED AT 400 WORDS)

Focal electrical stimulation in the midbrain periaqueductal gray (PAG) or medullary nucleus raphe magnus (NRM) inhibits spinal nociceptive transmission and nociceptive reflexes. The purpose of this study was to evaluate, in lightly pentobarbital-anesthetized rats, the spinal neurotransmitter(s) mediating descending inhibition of the nociceptive tail-flick (TF) reflex produced by focal electrical stimulation in the PAG or NRM. To characterize the neurotransmitter(s) mediating inhibition of the TF reflex, selective pharmacologic antagonists were administered into the lumbar intrathecal space. Stimulation thresholds in the PAG or NRM for inhibition of the TF reflex were established and the effects of intrathecally administered phentolamine, yohimbine, prazosin, methysergide (15 micrograms initially, 30 micrograms cumulative) or naloxone (10 micrograms initially, 20 micrograms cumulative) on TF inhibitory thresholds determined. Phentolamine, yohimbine and methysergide increased the intensity of stimulation in the PAG and the NRM for inhibition of the TF reflex; prazosin and naloxone had no effect. Descending inhibition produced by focal electrical stimulation in the PAG or NRM is mediated in part by spinal serotonergic and/or alpha 2-adrenergic receptors. Naloxone was administered both intrathecally and intravenously; however, a role for opioid receptors in descending inhibition from the midbrain or medulla was not found.

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Several lines of evidence have demonstrated a role for the lateral hypothalamus (LH) in an endogenous system of descending inhibition. The present study, in rats lightly anesthetized with pentobarbital, was undertaken to examine systematically the organization in the brain stem of pathways mediating descending inhibition of the nociceptive tail flick (TF) reflex produced by focal electrical stimulation in the LH. The microinjection of lidocaine into the midbrain, dorsolateral pons, or medial medulla resulted in significant increases in stimulation thresholds in the LH for inhibition of the TF reflex (89.1, 67.4, and 73.6%, respectively). Selective lesions of cell bodies in the midbrain or medulla by the neurotoxin ibotenic acid also produced significant increases in stimulation thresholds in the LH for inhibition of the TF reflex (31.6 and 131.6%, respectively), thus revealing relays in the periaqueductal gray and the nucleus raphe magnus located between the LH and the lumbar spinal cord. The failure of ibotenic acid to affect LH-produced descending inhibition when microinjected into the dorsolateral pons, and the significant effect produced by lidocaine microinjected into the same area, implicates fibers of passage in the dorsolateral pons in descending inhibition of the TF reflex produced by focal electrical stimulation in the LH. The fluorescent dye Fast blue and HRP conjugated to wheat germ agglutinin were used to confirm that the area stimulated in the LH has reciprocal connections with the periaqueductal gray and nucleus raphe magnus.

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