Pharmacology Notes

Receptors for opioid drugs and endogenous opioid peptides are located on the synaptic membranes of neurones in the brain and the spinal cord, as described above. There is also evidence for opioid receptor expression in some peripheral inflammatory states (eg inflammatory arthropathies).

Three distinct classes of opioid receptor (mu, delta and kappa) are described on the basis of their binding characteristics and selective sensitivities to different opioids. Another opioid-related receptor is the opioid receptor-like 1 (ORL1) receptor. Its role is still being clarified, although its natural agonist, nociceptin, has been identified. The sigma receptor is no longer considered a subtype of opioid receptor.

In the spinal cord, mu (70%), delta (24%) and kappa (6%) receptors are found at presynaptic and postsynaptic sites. Nociceptive input to the spinal cord is inhibited by drugs activating mu-opioid receptors on small primary afferent fibre terminals. Delta-opioid receptors mediate anti-nociception at spinal (delta-1) and supraspinal (delta-2) sites. The analgesic role of kappa-opioid receptors in the spinal cord is complex and not fully defined.

Within the brain, opioid receptors mediate effects on the limbic system, hypothalamus, pituitary and brainstem. Mu receptor agonist effects include miosis, respiratory depression, bradycardia, hypothermia, euphoria or indifference, and both spinal and supraspinal anti-nociception. Delta opioids produce mydriasis, stimulation of respiration, tachycardia, and delirium, and modestly reduce nociceptive responses, although they also markedly potentiate mu-opioid induced analgesia. Kappa opioids produce miosis, dysphoria, sedation and some spinal anti-nociception.

Outside the CNS, opioid receptors are widespread in the gut, explaining the constipating effect of opioid drugs, and in peripheral tissues, where opioids have a role in modifying inflammation.

The endogenous opioid peptides consist principally of enkephalins, beta endorphin and dynorphins, with additional opioid-like peptides also found in the CNS. Each peptide family is derived from a genetically distinct precursor polypeptide and has a characteristic anatomical distribution. In general, enkephalins have a higher affinity for delta receptors, beta endorphin has a higher affinity for mu receptors, and dynorphin a higher affinity for kappa receptors.

Opioid drugs and the endogenous opioid peptides have different receptor affinities. Morphine is a strong mu receptor agonist, with some agonist activity at kappa-opioid receptors; analgesia is associated with activation of these receptors. The different receptor affinities of otherwise similar mu-opioid agonists may explain the benefits sometimes achieved by opioid rotation in reducing tolerance in long-term opioid therapy. Drugs with both agonist and antagonist actions at the receptor (eg pentazocine, buprenorphine), when administered in conjunction with other conventional opioids, can limit the analgesic action of opioid agonists and may even produce withdrawal effects.

One of the more significant difficulties with opioid analgesia in subacute and chronic settings is the development of tolerance, which occurs within days to weeks (or even sooner) of repeated or continuous exposure. The mechanisms of tolerance include desensitisation of opioid receptors and a shift of descending modulation towards facilitation rather than inhibition.

Alpha-2-adrenergic agonists have a range of effects including sedation, centrally mediated hypotension and analgesia. The clinical utility of clonidine as an adjunctive therapy in anaesthesia and pain medicine has become well established. The alpha-2-selective agonists clonidine and more recently dexmedetomidine have been demonstrated to have anti-nociceptive effects when administered either systemically or intrathecally. A presynaptic site of action of alpha-2-adrenoceptor agonists had been identified for many of the effects of these agents, and a presynaptic location also results in an autoregulatory effect via negative feedback in adrenergic nerve terminals.

Agents such as cocaine and amitriptyline potentiate opioid-induced analgesia in part by enhancing alpha-2-adrenoceptor activity because they inhibit neuronal noradrenaline reuptake.

Opioids and alpha-2-adrenoceptor agonists have a close interaction. Synergistic anti-nociceptive effects have been documented, as has the development of tolerance.

There are many other sites for analgesic drug action within the CNS. Most drugs that act on these sites also have nonspecific effects elsewhere in the brain, limiting their effective use as analgesics: