Neuropharmacology: Studies of Narcotic Drugs

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CHOLINERGIC MECHANISMS IN NARCOTIC ANALGESICS

V.L. MEHTA,     Department of Pharmacology, University College of Medical Sciences, Ring Road, New Delhi 110016, India

Publisher Summary

In the last few years, there has been renewed interest in the neurotransmitter acetylcholine (ACh), regarding its involvement in the ascending system of cholinergic neurons, which plays an important role in attention, awareness, and consciousness. Elucidation of the mechanism of action of morphine through cholinergic neurons has been the subject of study of various workers. It was shown that morphine inhibited the release of ACh from electrically stimulated guinea-pig ileum, possibly by an effect on postganglionic elements; also from cat superior cervical ganglion; and from neuromuscular junctions such as rat diaphragm and sartorius muscle. The effect of an antagonist that reverses the depression in ACh release produced by morphine presumably involves removal or displacement of morphine from the tissue sites that it normally occupies; this removal in turn leads to the increase in ACh release. This increased ACh release in the brain may partly be responsible for the hyperactive state that follows the acute withdrawal of morphine in animals. In view of this, it is interesting to note that the use of ACh antagonists has been recommended to ameliorate the abstinence syndrome and chlorpomazine has been used and recommended for the treatment of the narcotic withdrawal syndrome.

In the last few years there has been renewed interest in the neurotransmitter acetylcholine (ACh), regarding its involvement in the ascending system of cholinergic neurones (SHUTE and LEWIS, 1965), which plays an important role in attention, awareness and consciousness. The progress in this field has been rather slow because of the lack of a sufficiently sensitive and specific chemical method for the estimation of ACh. However, recently it has been made possible to estimate picogram quantities of ACh in tissue samples and fluids by the use of a combination of gas chromatography and mass spectrometry. This has led to studies on ACh metabolism, storage and release and also has proved beyond doubt the identity of biologically active cholinergic substances present in brain nuclei (KOSLOW, RACAGNI and COSTA, 1974).

Various putative neurotransmitters such as catecholamines, serotonin and ACh have been implicated in the mechanism of the analgesic action of morphine and related compounds and their interaction with antagonists like nalorphine. Although the first narcotic antagonist was described as early as 1915, it was only with the appearance of nalorphine in the early 1940s (HART, 1941) that an effective morphine antagonist became available. Nalorphine not only antagonized the actions of morphine but had an analgesic activity of its own. The latter aspect of nalorphine action was eventually ignored. It was also found that nalorphine had a remarkably less addicting liability than morphine. This prompted the interest in the field of narcotic antagonist analgesics. Today a wide spectrum of narcotic analgesic compounds ranging from pure agonists to pure antagonists are available.

Elucidation of the mechanism of action of morphine through cholinergic neurones has been the subject of study of various workers. It was shown that morphine inhibited the release of ACh from electrically stimulated guinea-pig ileum, possibly by an effect on postganglionic elements (PATON, 1957; SCHAUMANN, 1957) and also from cat superior cervical ganglion (PELIKAN, 1960) and neuromuscular junctions such as rat diaphragm and sartorius muscle (FREDERICKSON and PINSKY, 1971). Several workers have estimated whole brain ACh content of smaller animals, and its release from the brain of anaesthetised and unanaesthetised animals. The administration of morphine increased the brain ACh content of rat brain (GIARMAN and PEPEU, 1962; HANO, KANETO, KAKUNAGA and MORIBAYASHI, 1964; MAYNERT, 1967; LARGE and MILTON, 1970), rat brain cortical slices (SHARKAWI and SCHULMAN, 1969), mouse brain after acute administration (HARRIS, 1970) and after chronic administration (MAYNERT, 1967; HOWES, HARRIS, DEWEY and VEYDA, 1969) and frog brain and spinal cord (NISTRI and PEPEU, 1973).

Most workers have estimated whole brain ACh content. This may not give a clear idea concerning the changes in its concentration in smaller areas and there is a possibility that even a very large increase in one anatomical region of the brain could be masked in whole brain assay. For example, TAKAHASHI, NASU, TANURA and KARIYA (1961) reported that chlorpromazine did not increase the ACh content of rat brain but MALHOTRA and PRASAD (1968) found that there was an increase of ACh content in the frontal cortex with chlorpromazine, suggesting that small changes in certain specific areas could not be detected by estimating ACh in whole brain. Moreover, the effect of morphine is known to be synergistic with the action of anaesthetics (SOLLMAN, 1957). It, therefore, appeared possible that the effects of morphine in anaesthetized animals might differ from those in unanaesthetized preparations. In order to overcome the effect of anaesthesia, the encéphale isolé preparation of the cat was employed in our experiments.

It was found that morphine sulphate (5 mg/kg) increased ACh content in almost all areas of the brain except the midbrain, in which a slight decrease was observed. The maximum increase was seen in the frontal cortex and hypothalamus (Table 1). WIKLER (1950, 1958) suggested that the analgesic action of morphine was similar to that seen after prefrontal lobectomy. Chlorpromazine has also been reported to produce an action similar to prefrontal lobectomy, and is also known to increase ACh content in the frontal cortex. Thus, it can be postulated that the withdrawal symptoms after chronic administration of morphine may be due to a decrease of ACh content in the frontal cortex and the beneficial effect elicited by chlorpromazine in these cases (ZELSON, 1970) may be due to the restoration of ACh content in the frontal cortex. A higher dose of morphine (15 mg/kg) produced more pronounced effects on the ACh content of different areas of the brain (Table 1). The effect on the hippocampus was quite distinct. DOMINO (1962) showed that morphine produced qualitatively different actions on the limbic system from those seen with anti-anxiety agents such as barbiturates, meprobamate and chlordiazepoxide which are known to raise the current threshold, to elicit evoked potentials and to shorten the duration of after-discharge. On the other hand, an analgesic dose of morphine changes the electrical activity of the amygdala and hippocampus produced by peripheral stimulation (JAFFE, 1970). This is consistent with the clinical observation that usual doses of opioids reduce the affective response to nociceptive stimulation and increase pain tolerance without altering the threshold for the perception of