pyrimidinones and Morphine-Dependence

In virtually all fur-coated and feathered animals, shaking movements of the body, similar to that made by a dog when wet, occur in response to irritation of the skin or in response to sensations of intense cold. Vigorous shaking movements occur in rats undergoing opiate withdrawal. I was led by this observation to investigations on the pharmacology of agents that stimulate or inhibit shaking. Thyrotropin-releasing hormone, injected centrally at submicrogram doses, produced in nondependent, barbiturate-anesthetized animals, shaking behavior identical in its general features to that of morphine withdrawal. AG-3-5 (1-[2-hydroxyphenyl]-4[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one), another chemical stimulant of shaking, produced specific sensations of cold in man by a peripheral site of action. In this context, it should be noted that sensations of cold, and the associated emotional discomfort, are conspicuous symptoms of opiate withdrawal in man. Shaking movements elicited by a variety of stimuli were inhibited by central administration of nanomolar doses of drugs that act as agonists on opiate, muscarinic, and alpha-adrenergic receptors. These observations may provide information on a) the identity of substances in brain that, when released, provoke opiate withdrawal signs and symptoms; b) the chemical nature of substances that stimulate peripheral cold receptors; and c) the pharmacologic classification of centrally acting agents that attenuate withdrawal and produce antinociception.

Topics: Animals; Cold Temperature; Escape Reaction; Humans; Morphine Dependence; Naloxone; Pentobarbital; Pyrimidinones; Rats; Receptors, Adrenergic, alpha; Receptors, Muscarinic; Receptors, Opioid; Sensation; Shivering; Structure-Activity Relationship; Substance Withdrawal Syndrome; Thyrotropin-Releasing Hormone

RX 336-M (7,8-dihydro-5',6'-dimethylcyclohex-5'-eno-1',2',8',14 codeinone) and four other chemically-diverse agents--AG-3-5 (1-[2-hydroxyphenyl]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one), Sgd 8473 (alpha-[4-chlorobenzylideneamino)-oxy]-isobutyric acid), thyrotropin releasing hormone (TRH), and sodium valproate--each induce signs of withdrawal, most notably 'wet-dog' shaking, after acute i.p. administration in drug-naive rats. They are therefore additions to a recently recognized and, as yet, ill-defined class of behaviorally active compounds. The pharmacological baselines that link these disparate agents together have been studied in the present work, using 'wet-dog' shaking as the behavioral measure and RX 336-M as the reference shake-inducing compound. Peripheral administration of clonidine, haloperidol, d-lysergic acid diethylamide, or morphine suppressed chemically induced shaking: naloxone had no marked effect. Reverse tolerance was associated with TRH-induced shaking whereas tolerance occurred with the other four compounds. Cross-tolerance interactions were asymmetrical. Thus, rats rendered tolerant to RX 336-M were cross-tolerant to AG-3-5, TRH, and sodium valproate but not to Sgd 8473; in contrast, RX 336-M-induced shaking was only significantly reduced in rats made tolerant to Sgd 8473. In view of the unidirectional nature of the cross-tolerance relationships studied, it is concluded that AG-3-5, Sgd 8473, sodium valproate, and TRH initiate 'wet-dog' shaking through neural substrates that differ from the one(s) associated with RX 336-M. Nevertheless, all five compounds may eventually trigger a common shake-inducing mechanism.

Topics: Animals; Codeine; Drug Tolerance; Humans; Hydroxamic Acids; Male; Morphine Dependence; Pyrimidinones; Rats; Shivering; Structure-Activity Relationship; Substance Withdrawal Syndrome; Thyrotropin-Releasing Hormone; Valproic Acid

1. Structure-activity relationship studies with new semi-synthetic isomorphine derivatives revealed that substitution of an azido group in position 6 (azidomorphines) greatly increases the analgesic potency whereas tolerance and dependence liability tend to decrease. 2. Azidomorphine (6-deoxy-6-azidodihydroisomorphine) and 14-hydroxyazidomorphine (6-deoxy-6-azidodihydro-14-hydroxyisomorphine) being in animal tests 40-300 times more potent than morphine, are the most effective analgesics among the semi-synthetic morphine alkaloids. 3. As demonstrated on mice, rats and rhesus monkeys, a remarkable dissociation between the analgesic potency and physical dependence capacity was the result of the introduction of the 6-azido group into dihydroisomorphine. 4. A dichotomy between analgesic effect and tolerance and addiction liability was demonstrated with azidomorphine also in man and the new substance proved to exert significantly less untoward effects than either morphine or pentazocine. 5. Rymazolium (Probon) a new non-narcotic analgesic which strongly potentiates the analgesic and antagonizes the respiratory depressant effect of morphine alkaloids in animals proved to hinder the development of tolerance to morphine in animals and man. 6. The azidomorphine-rymazolium association was found to be less respiratory depressant than azidomorphine administered alone. In patients with chronic intractable pain, an association of azidomorphine (0.5 mg) and rymazolium (150 mg) achieved total pain relief without noticeable euphoria and none of the twelve patients showed, according to the Himmelsbach scoring system, acute abstinence syndromes after nalorphine administration.

Topics: Analgesics; Analgesics, Opioid; Animals; Drug Synergism; Drug Tolerance; Humans; Macaca mulatta; Mice; Morphine Dependence; Morphine Derivatives; Pyrimidinones; Rats