naloxazone and Pain

Topics: Analgesia; Animals; Cold Temperature; Deoxyglucose; Endorphins; Hyperphagia; Hypophysectomy; Hypothalamus; Morphine; Naloxone; Pain; Physical Exertion; Rats; Rats, Brattleboro; Sensory Thresholds; Stress, Physiological; Vasopressins

We have synthesized a novel derivative of naloxone, naloxyl-6 alpha-spirohydantoin. The compound was rigorously purified and its stereochemical structure characterized. In tests in vivo in mice, it was less toxic than the parent compound and it showed weak anticonvulsive activity. It exerted antagonist effects comparable to those of naloxone but its effects were longer lasting, persisting for a week.

Topics: Animals; Anticonvulsants; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Receptors, Opioid

The long-acting opiate antagonistic potency of naloxazone (NXZ), beta-chlornaltrexamine (beta-CNA) and beta-funaltrexamine (beta-FNA) was compared using three inbred strains of mice, in which morphine induces either analgesia (DBA/2), locomotion (C57BL/6), or both responses (C3H/He). The antagonists were applied SC 24-120 hr before morphine (10 or 20 mg/kg, IP), followed by the tests after 30 min. The minimal dose which completely antagonized morphine-induced analgesia in DBA and locomotion in C57 mice during 24 hr were: for NXZ 50 and 100 mg/kg, for beta-CNA 0.8 and 6.2 mg/kg, for beta-FNA 1.6 and 12.5 mg/kg, respectively. beta-FNA and beta-CNA more potently blocked morphine-induced analgesia in DBA mice than the activity response in the C57 strain. In contrast, beta-FNA prevented morphine-induced locomotion at a lower dose (6.2 mg/kg) than analgesia (greater than 50 mg/kg) in C3H mice, while beta-CNA was equipotent (1.6 mg/kg). In general, beta-CNA turned out to be the most reactive compound, antagonizing morphine effects in low doses up to 120 hr. beta-FNA selectively antagonized either morphine-induced analgesia or locomotion, depending on the strain used. This suggests that a given morphine response might be caused by a genetically determined multiplicity of opiate receptor types and their mutual interactions.

Topics: Animals; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Morphine; Motor Activity; Naloxone; Naltrexone; Pain; Species Specificity

Administration of naloxazone, a hydrazone derivative of naloxone, to intact mice produces a prolonged inhibition of in vitro [3H]opiate binding lasting up to 3 days. The effect is selective since naloxazone treatment produces no changes in alpha or beta adrenergic, muscarinic or benzodiazepine receptor binding and the effects on opiate binding sites are not reproduced by non-narcotic hydrazines. Scatchard analyses of saturation experiments 24 hr after in vivo naloxazone treatment show an absence of high affinity binding sites of [3H]naloxone, [3H]dihydromorphine and 2-D-[3H]ala-met-enkephalinamide, although low affinity sites are relatively unaffected. Blockade of high affinity sites by naloxazone produces an 11-fold increase in the ED50 value for morphine analgesia at 24 hr with both tailflick and writhing assays. By contrast, naloxazone produces no change in the LD50 value for morphine. As high affinity binding returns to control levels over 3 days, ther ED50 for morphine analgesia in naloxazone-pretreated mice returns to control values. Accordingly, the analgetic, but not lethal, effects of morphine may be mediated by the high affinity subpopulation of opiate receptors.

Topics: Analgesics, Opioid; Animals; Binding, Competitive; History, 18th Century; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Narcotic Antagonists; Pain; Rats; Receptors, Opioid