Azidomorphine

Abstract: In rats, an ED50 for analgesia of morphine, meperidine, viminol R2 or azidomorphine decreases the turnover rate of acetylcholine (TRACh) in cortex and hippocampus. These four analgetics fail to change to TRACh in striatum when given in a dose range from ED30 for analgesia up to a cataleptic dose. Viminol S2, a nonanalgesic stereoisomer of vimonol R2, fails to decrease the TRACh in cortex and hippocampus. Naltrexone, an opiate antagonist, also fails to change the cortical and hippocampal TRACh but it antagonizes the decrease in cortical and hippocampal TRACh elicited by the four analgetics. Since the ED50 of these four analgetics fails to change the TRACh in striatum which contains a high density of opiate receptors and intrinsic cholinergic neurons, but decreases the TRACh in hippocampus and cortex which contain a low density of opiate receptors, it can be inferred that opiate receptors are not exclusively involved in the regulation of TRACh. However, the results suggest that certain cholinergic pathways participate in the mediation of analgesia.

Abstract: Sixteen opioid agonists were studied for their capacity both to maintain responding previously reinforced by codeine and to suppress the withdrawal syndrome induced by morphine deprivation in rhesus monkeys. All compounds, which included examples from each of the major chemical families of opioids, maintained responding at rates above those maintained by saline. There were differences among the compounds in the maximal response rates maintained, and large differences in their potencies in maintaining responding. In morphine-dependent monkeys, the abstinence signs that developed 14 h after the last morphine dose were suppressed completely by all of the compounds except codeine. There was a strong positive correlation (r=0.92) between the potency of a compound in maintaining drug-reinforced responding and the potency of the compound in suppressing the morphine withdrawal syndrome.

Abstract: From a series of newly synthesized morphine derivatives 6-deoxy-6-azidodihydroisomorphine (azidomorphine) and 6-deoxy-6-azidodihydroisocodeine (azidocodeine) were selected for detailed pharmacological study. In the hot plate test in rats, azidomorphine proved to be about 300 times and azidocodeine about 13 times more potent than morphine. Azidomorphine given over ten weeks was significantly less toxic in the rat than morphine or fentanyl. A total dose 40 times that of the analgesic ED50 dose of morphine (200 mg kg−1) produced the highest grade physical dependence in mice as measured by naloxone-precipitated jumping. However, even a total dose of 2800 times the analgesic ED50 dose of azidomorphine (70 mg kg−1) was less effective in producing physical dependence. Treatment on every second day with increasing doses of morphine led to the development of high grade tolerance and chronic physical dependence in rats and monkeys (Rhesus macacus). Severe abstinence syndrome was precipitated after the administration of nalorphine in rats pretreated for 24 days with rapidly increasing doses of morphine and grave symptoms of abstinence were elicited in pretreated monkeys on withdrawal of morphine on the 55th, 175th and 300th days of treatment. In parallel experiments neither the development of tolerance nor that of physical dependence was demonstrable in rats and monkeys pretreated with increasing equi-analgesic doses of azidomorphine.