Effects of naltrexone on the binding of [3H]D-Ala2, MePhe4, Gly-ol5-enkephalin to brain regions and spinal cord and pharmacological responses to morphine in the rat.

1. The effects of naltrexone pellet implantation and removal on the analgesic and hypothermic effects of morphine and the binding of 3H-D-Ala2, MePhe4, Gly-ol5-enkephalin (DAMGO) to mu-opiate receptors in rat brain regions and spinal cord were determined. 2. Male Sprague-Dawley rats were implanted subcutaneously with a pellet containing 10 mg of naltrexone for 7 days. Placebo pellet implanted rats served as controls. The pellets were removed on day 8, and the analgesic and hyperthermic effects were determined in the rat 24 hr later. Morphine produced a dose-dependent analgesic and hyperthermic responses in rats implanted with placebo pellets. Enhanced analgesic and hyperthermic responses to morphine were produced in rats implanted with naltrexone pellets. 3. The binding constants (Bmax and Kd values) of [3H]DAMGO in regions of the brain (amygdala, hypothalamus, striatum, midbrain, hippocampus, pons + medulla and cortex), and spinal cord of rats with naltrexone pellet left intact or removed were determined. The Bmax values of [3H]DAMGO were increased in all brain regions and spinal cord of rats in which the naltrexone pellets were left in place or removed prior to sacrificing. However, the Kd values of [3H]DAMGO were unaffected by naltrexone treatment. 4. It is concluded that enhanced analgesic and hyperthermic response to morphine is produced in rats implanted with naltrexone pellets and such alterations in the pharmacological responses are due to up-regulation of mu-opiate receptors in all the brain regions and spinal cord. Additionally whether the pellets were left intact (receptors blocked) or removed (receptors not blocked), the mu-opiate receptors were up-regulated in spinal cord and all the regions of the brain.