https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1959.sp006233

A study of supersensitivity in denervated mammalian skeletal muscle.

Muscarinic receptor subtypes: M1 and M2 biochemical and functional characterization

Cholinergic mechanisms in the control of behavior by the brain.

Opiates are among the oldest medications available to manage a number of medical problems. Although pain is the current focus, early use initially focused upon the treatment of dysentery. Opium contains high concentrations of both morphine and codeine, along with thebaine, which is used in the synthesis of a number of semisynthetic opioid analgesics. Thus, it is not surprising that new agents were initially based upon the morphine scaffold. The concept of multiple opioid receptors was first suggested almost 50 years ago (Martin, 1967), opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain. Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years. Early pharmacological studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes—primarily through the synthesis of novel agents. These chemical biologic approaches were then eclipsed by the molecular biology revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated.

Mu Opioids and Their Receptors: Evolution of a Concept

1. The origin of the co-ordination and rhythm of mastication provoked by electrical stimulation of the putamen and corticobulbar pathways was studied in the rabbit.

2. Bursts of activity were recorded from the mandibular and hypoglossal nerves and the hypoglossal nucleus, which were in phase with the observed masticatory movements. Discharges occurred alternately in nerves to jaw-opening and jaw-closing muscles.

3. The rate of burst discharges was not altered by paralysis, or by large variations in the stimulation frequency.

4. Regularly recurring bursts of activity continued to occur in the hypoglossal nucleus in response to random frequency stimulation after severing branchial nerves, cervical nerves and the spinal cord of paralysed rabbits.

5. Mechanical deformation of the brain of vascular or respiratory origin was discounted as the origin of the rhythm.

6. It is concluded that mastication is controlled by a brain-stem pattern generator which can be activated by adequate inputs from certain higher centres and, as concluded in other studies, from the oral cavity itself.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1971.sp009454

Evidence for central timing of rhythmical mastication

A comparison of the effects obtained with N -allyl-normorphine and with morphine shows that N -allyl-normorphine is about as toxic, but much less effective than morphine in raising the threshold for pain in mice. In contrast to morphine small doses do not depress the respiration; very large doses, however, cause arrest of the respiration, and all animals succumbing to N -allyl-normorpine die of respiratory failure. N -allyl-normorphine prevents or abolishes the action of morphine. Premedication with this substance increases the resistance of mice to morphine so that otherwise lethal doses are tolerated without untoward effects. Furthermore, an injection of N -allyl-normorphine prior to that of morphine prevents analgesia (mice), respiratory depression (rabbits), and the general depressing (dogs) and stimulatory (cats) effects as well. If morphine is administered in the first place, a subsequent injection of N -allyl-normorphine abolishes its analgesic effect (mice) restores the depressed respiration to its previous level (rabbits) and abolishes its toxic manifestations in cats and dogs. The reduction in the mortality of morphine poisoning in mice by N -allyl-normorphine further demonstrates the effectiveness of this substance as an antidote against morphine. Since the site of action of morphine is generally assumed to be central, it would appear that N -allyl-normorphine by virtue of its chemical relationship to morphine exerts its action upon the same centers as morphine rendering them less sensitive to morphine. This assumption would offer the most plausible explanation for the observations reported.

Antagonistic effect of n-allyl-normorphine upon morphine

Evaluation of curarizing drugs in man

Chlorpromazine has been characterized with rabbit aortic strips as a slowly reversible adrenergic blocking agent. Chlorpromazine increased the magnitude and markedly prolonged the pressor response to levarterenol while depressing the magnitude of the response to l -epinephrine. Chlorpromazine sulfoxide enhanced the magnitude and prolonged the duration of the levarterenol-induced blood pressure rises and tachycardia; it prolonged the duration of l-epinephrineevoked tachycardia and pressor responses, It has been proposed that chiorpromazine has two dissociable actions on epinephrine and levarterenol. It (1) blocks the adrenergic receptor and (2) depresses some deactivating process. Chlorpromazine did not significantly alter the uptake of either l -epinephrine or levarterenol by the red blood cell; it did not significantly alter inactivation of these amines by liver slices.

Chlorpromazine iii. the effects of chlorpromazine and chlorpromazine sulfoxide on vascular responses to l-epinephrine and levarterenol

The effect of the brain stem reticular formation on the linguomandibular reflex.

Quantification of the effects of different CNS depressants on the EEG activation response evoked by electrical stimulation of the medial reticular formation has been studied in encephale isole cat preparations.

Quantitative relationships were established between stimulus strength and the EEG activation response, and dose-response curves were constructed for atropine, atropine methylnitrate, pentobarbital and chlorpromazine.

Depression of the EEG activation could be demonstrated with threshold doses of 0.2 mg/kg for atropine and 1 mg/kg for atropine methylnitrate. The threshold dose for chlorpromazine was 0.5 mg/kg and for pentobarbital, 1 mg/kg.

Atropine methylnitrate was found to have an action on the CNS similar to that of atropine; its low potency and latency of action may be attributed to the slow diffusibility of the quaternary nitrogen configuration.

Klaus Unna

Papers

Antagonistic effect of n-allyl-normorphine upon morphine

Evaluation of curarizing drugs in man

Chlorpromazine iii. the effects of chlorpromazine and chlorpromazine sulfoxide on vascular responses to l-epinephrine and levarterenol

The effect of the brain stem reticular formation on the linguomandibular reflex.

Quantification of effects of depressant drugs on EEG activation response.