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Opioid drugs, typified by morphine, produce their pharmacological actions, including analgesia, by acting on receptors located on neuronal cell membranes. The presynaptic action of opioids to inhibit neurotransmitter release is considered to be their major effect in the nervous system. Recent advances in the molecular biology of opioid receptors has confirmed that there are 3 types of opioid receptor, m, d and k. All are coupled to intracellular mechanisms via G-proteins. The discovery of the molecular structure of opioid receptors provides more precise approaches for the study of opioid pharmacology. These should lead to the development of new drugs for therapeutic use. Introduction Major advances have been made in understanding the mechanism of action of the opioids. The most important recent advances have been the cloning and characterisation of the receptors acted upon by opioids (opioid receptors), increased knowledge of the cellular action of opioids and identification of the sites of action of opioids in the brain. Opioid receptors Pharmacological studies have shown that the naturally -occurring opioid peptide, b endorphin, interacts preferentially with m receptors, the enkephalins with d receptors and dynorphin with k receptors (Table 1). Morphine has considerably higher affinity for m receptors than for other opioid receptors. The opioid antagonist, naloxone, inhibits all opioid receptors, but has highest affinity for m receptors. All 3 receptors produce analgesia when an opioid binds to them. However, activation of k receptors does not produce as much physical dependence as activation of m receptors.
The opioid receptors and many other membrane receptors are coupled to guanine nucleotide binding proteins known as G-proteins. G-proteins consist of 3 subunits (a, b and g). When the receptor is occupied, the a subunit is uncoupled and forms a complex which interacts with cellular systems to produce an effect (Fig. 2).
Several types of G-proteins have been found. The types to which the opioid receptors are coupled produce inhibitory effects in neurons. Sites of action of opioids on neurons The nervous system comprises neurons of many different types which differ in size, shape, function and the chemical nature of the neurotransmitters released from their terminals to carry information to other neurons. Morphine, by an action on m receptors, inhibits release of several different neurotransmitters including noradrenaline, acetylcholine and the neuropeptide, substance P. Opioids and pain pathways Opioid receptors are present in many regions of the nervous system that are involved in pain transmission and control, including primary afferent neurons, spinal cord, midbrain and thalamus. The physiological role of naturally occurring opioid peptides in regulating pain transmission is not clear. However, under pathological conditions, the endogenous opioid system is activated. The opioid drugs produce analgesia by actions at several levels of the nervous system, in particular, inhibition of neurotransmitter release from the primary afferent terminals in the spinal cord and activation of descending inhibitory controls in the midbrain. A major advance in understanding pain mechanisms has been the recognition that ongoing activity in nociceptive pathways may lead to profound alterations in the levels of neurotransmitters in primary afferent neurons and to changes in sensitivity to opioid analgesia. Thus, neuropathic pain is associated with reduced opioid sensitivity, whereas inflammatory pain may be associated with increased sensitivity to opioids. Furthermore, the changes that occur in pain sensitivity in chronic pain states have been attributed to activation of the glutamate NMDA receptor. Opioid inhibition of neurotransmitter releasese
Decreased Ca++ entry Increased outward movement of K+ Inhibition of adenylate cyclase Tolerance and dependence Although dependence usually accompanies tolerance, they are distinct phenomena. Dependence is masked until the opioid drug is removed from its receptors, either by stopping the drug or by giving an opioid receptor antagonist such as naloxone. A withdrawal or abstinence response then occurs. The withdrawal response is very complex and involves many brain regions. Dependence occurs much more rapidly than tolerance, and naloxone-precipitated withdrawal can be seen after a single dose of morphine in humans. Adenylate cyclase has long been implicated in opioid withdrawal and increased adenylate cyclase activity following chronic morphine treatment has been observed in the locus ceruleus, a central noradrenergic cell group which is considered to play a major role in opioid withdrawal. However, the mechanisms involved in other brain regions remain to be elucidated. Conclusion Further reading Reisine T, Bell GI. Molecular biology of opioid receptors. Trends Neurosci 1993;16:506-10. Dickenson AH. Where and how do opioids act? Proceedings of the 7th World Congress on Pain. In: Gebhart GF, Hammond DL, Jensen TS, editors. Progress in pain research and management, Vol. 2. Seattle: IASP Press, 1994:525-52. |