Focal κ-opioid receptor-mediated dependence and withdrawal in the nucleus paragigantocellularis

The nucleus paragigantocellularis (PGi) has been hypothesized to play an important role in the development of physical dependence on opioids, including the prototype μ-opioid receptor agonist, morphine, and the mixed agonist/antagonist, butorphanol, which shows selective κ-opioid receptor agonist activity, in rats. In confirmation of previous work, electrical stimulation of the PGi in opioid-naı̈ve rats induced stimulus-intensity-related, withdrawal-like behaviors similar to those observed during naloxone-precipitated withdrawal from dependence upon butorphanol. Novel findings were made in rats surgically implanted with cannulae aimed at the lateral ventricle and the right PGi and made physically dependent by intracerebroventricular infusion of either morphine (26 nmol/μl/h) or butorphanol (26 nmol/μl/h) through an osmotic minipump for 3 days. Two hours following termination of the opioid infusion, microinjections of naloxone (11 nmol/400 nl), a nonselective opioid receptor antagonist, or nor-binaltorphimine (nor-BNI) (3.84 nmol/400 nl), a selective κ-opioid receptor antagonist, were made into the PGi of morphine-dependent and butorphanol-dependent rats. Discrete PGi injections precipitated withdrawal behaviors, with significant (P<.05) increases noted in the incidence of teeth chattering, wet-dog shakes, and scratching. Composite scores for behavioral withdrawal were significantly higher in nor-BNI-precipitated, butorphanol-dependent rats (score=6.8±0.6), in naloxone-precipitated, butorphanol-dependent rats (8.9±0.8), and in naloxone-precipitated, morphine-dependent rats (11.5±0.9) than in all other groups. Both κ- and μ-opioid receptor mediated dependence can be demonstrated at the level of a discrete medullary site, the PGi, which further supports a specific role for this nucleus in elicitation of behavioral responses during opioid withdrawal.