dihydromorphine and Substance-Withdrawal-Syndrome

The densities of brain alpha 2-adrenoceptors and mu-opioid receptors, quantitated by means of the binding of the agonists [3H]clonidine and [3H]dihydromorphine, respectively, were studied during the development of morphine dependence and spontaneous withdrawal in the rat. The oral administration of morphine (12-130 mg/kg for 3-21 days) led to inconsistent changes in alpha 2-adrenoceptor density while the density of mu-opioid receptors was down-regulated. In contrast, spontaneous opiate withdrawal (3-72 h) significantly increased the density of alpha 2-adrenoceptors while the density of mu-opioid receptors was rapidly up-regulated to control values. In the hypothalamus, but not in other brain regions, the increase in alpha 2-adrenoceptor density after withdrawal followed a time course (3-72 h) related to the severity of the abstinence syndrome. Thus, there was a positive and significant correlation between the severity of withdrawal and the density of alpha 2-adrenoceptors in the hypothalamus. Short-term treatment with clonidine (2 x 0.5 mg/kg, i.p.) prevented the morphine withdrawal-induced increases in alpha 2-adrenoceptor density in various brain regions, but not in the hypothalamus. The main results suggest that modulation of hypothalamic alpha 2-adrenoceptor density during morphine withdrawal is a relevant physiological mechanism by which the opiate abstinence syndrome is counteracted.

Topics: Animals; Brain; Brain Stem; Cerebral Cortex; Clonidine; Corpus Striatum; Dihydromorphine; Hypothalamus; Male; Morphine; Morphine Dependence; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Opioid; Substance Withdrawal Syndrome

Stereospecific accumulation of [3H]dihydromorphine and [3H]naltrexone by striatal slices from morphine-dependent mice was examined in Krebs-Ringer bicarbonate medium. Striatal slices showed a saturable and stereospecific accumulation of both [3H]ligands. The accumulation constant of naltrexone, determined by Wilkinson's analysis, was significantly decreased in both morphine-dependent mice and dependent mice abruptly withdrawn for 6 hr. The maximal accumulation of naltrexone was not changed in withdrawn mice, but decreased in dependent mice. This could be due to the high concentration of residual morphine in the slices. There were no significant differences in the accumulation constant or maximal accumulation of dihydromorphine among the striatal slices from control, dependent and withdrawn mice. These data indicate that in morphine-dependent mice, there is an increased affinity of the opioid receptors for the narcotic antagonist, naltrexone but not for the agonist, dihydromorphine.

Topics: Animals; Binding, Competitive; Corpus Striatum; Dihydromorphine; Humans; In Vitro Techniques; Male; Mice; Morphine Dependence; Morphine Derivatives; Naloxone; Naltrexone; Receptors, Opioid; Stereoisomerism; Substance Withdrawal Syndrome

1. The opiate receptor binding to whole brain synaptic membranes obtained from mice subjected to acute and chronic morphine administration and precipitated withdrawal was investigated. 2. The number of high and low affinity binding sites was significantly higher in morphine tolerant group than in control; acute administration of morphine also induced an increase in the number of binding sites, though this increase was significantly lower as compared to tolerant group. 3. The affinity of both high and low affinity sites, however remained unchanged after acute or chronic treatment. In contrast, both the affinity and the number of binding sites were significantly reduced after precipitated withdrawal, compared to the tolerant group. 4. Sodium chloride enhanced the antagonist binding and inhibited the agonist binding in both tolerant and non-tolerant groups. 5. It is concluded that (a) the increase in the number of receptors during tolerance development is an extension of the acute effect of morphine, (b) the character of tolerant membrane is qualitatively same as that of non-tolerant membrane, (c) upon withdrawal, the receptor population is brought back to normal; the altered higher, affinity after withdrawal may be a compensatory effect as a corollary to the withdrawal-induced decrease in receptor population.

Topics: Animals; Binding, Competitive; Brain; Dihydromorphine; Drug Tolerance; Humans; Male; Mice; Mice, Inbred ICR; Morphine; Morphine Dependence; Naloxone; Receptors, Opioid; Sodium Chloride; Substance Withdrawal Syndrome; Synapses; Synaptic Membranes