Opioids - mechanisms of action (2022)

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.

The opioid drugs, typified by morphine, have the potential to produce profound analgesia, mood changes, physical dependence, tolerance and a hedonic ('rewarding') effect which may lead to compulsive drug use. Opioid drugs act in both the central and peripheral nervous systems. Within the central nervous system, opioids have effects in many areas, including the spinal cord. In the peripheral nervous system, actions of opioids in both the myenteric plexus and submucous plexus in the wall of the gut are responsible for the powerful constipating effect of opioids. In peripheral tissues such as joints, opioids act to reduce inflammation.

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
Opioids produce effects on neurons by acting on receptors located on neuronal cell membranes. Three major types of opioid receptor, m, d and k (mu, delta and kappa), were defined pharmacologically several years ago. Recently, the 3 opioid receptors have been cloned, and their molecular structures described. These receptors belong to the large family of receptors which possess 7 transmembrane-spanning domains of amino acids (Fig. 1).

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.

Fig. 1

Diagram of human m opioid receptor. Chains of amino acids are shown as black lines. The 7 transmembrane -spanning domains (each containing 20 or more amino acids) are shown as cylinders.

Opioids - mechanisms of action (1)
Table 1
Selectivity of naturally occurring opioid peptides and opioid drugs for opioid receptors
u Receptor
Opioid peptides
b endorphin
Opioid drugs
Partial/mixed agonists
± ± ±
± ±
± indicates partial agonist
The number of + or ± indicates potency

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).

Fig. 2

The function of G-proteins. Under resting conditions, guanosine diphosphate (GDP) is associated with the a subunit. When the opioid binds to the receptor, GDP dissociates from the a subunit and guanosine triphosphate (GTP) takes its place. This produces a conformational change that causes the opioid to dissociate from the receptor. The a subunit bound to GTP also dissociates from the b and g subunits and interacts with the system within the cell that produces the effect (the effector). The intrinsic enzymatic activity of the a subunit causes GTP to be converted back to GDP and the a subunit now reassociates with the b and g subunits to return the complex to its normal state.

Opioids - mechanisms of action (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
Opioids have actions at two sites, the presynaptic nerve terminal and the postsynaptic neuron. The postsynaptic actions of opioids are usually inhibitory. The presynaptic action of opioids is to inhibit neurotransmitter release, and this is considered to be their major effect in the nervous system. However, the final effect of an opioid in the brain is the result, not only of its action at multiple presynaptic sites on both inhibitory and excitatory neurons, but also of its postsynaptic effects. For example, presynaptic inhibition of neurotransmitter release may result in excitatory effects in a target neuron if the neurotransmitter normally produces an inhibitory effect. However, if the opioid also has a postsynaptic inhibitory effect on the target neuron, the excitatory effects may not occur. Thus, the location and density of opioid receptors on a neuron determines the overall effect of opioids on the neuron.

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
Pain is normally associated with increased activity in primary sensory neurons induced by strong mechanical or thermal stimuli, or by chemicals released by tissue damage or inflammation. Primary sensory neurons involved in pain sensation release predominantly substance P and glutamate in the dorsal horn of the spinal cord. Nociceptive information is transmitted to the brain via the spinothalamic tracts. This ascending information can activate descending pathways, from the midbrain periaqueductal grey area, which exert an inhibitory control over the dorsal horn.

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
Neurotransmitter release from neurons is normally preceded by depolarisation of the nerve terminal and Ca++ entry through voltage-sensitive Ca++ channels. Drugs may inhibit neurotransmitter release by a direct effect on Ca++ channels to reduce Ca ++ entry, or indirectly by increasing the outward K + current, thus shortening repolarisation time and the duration of the action potential. Opioids produce both of these effects because opioid receptors are apparently coupled via G-proteins directly to K+ channels and voltage-sensitive Ca++ channels. Opioids also interact with other intracellular effector mechanisms, the most important being the adenylate cyclase system (Fig. 3).

Fig. 3

Opioids have been proposed to inhibit neurotransmitter release by inhibiting calcium entry, by enhancing outward movement of potassium ions, or by inhibiting adenylate cyclase (AC), the enzyme which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).

Opioids - mechanisms of action (3)

Decreased Ca++ entry
Voltage-sensitive channels are activated only when there is depolarisation of the neuron. Three types of voltage-sensitive Ca++ channels are known, the L-type (large conductance) sensitive to calcium channel blockers, the T-type (small conductance) and the N-type (intermediate conductance). Opioids inhibit N-type Ca++ channels and thus inhibit neurotransmitter release. This effect alone does not account fully for the effect of opioids on neurotransmitter release.

Increased outward movement of K+
Many types of K+ channels are now known, some of which are voltage-sensitive and others which are sensitive to intracellular substances. Opioids open voltage-sensitive K+ channels and thus increase outward movement of K+ from neurons. This effect occurs in several brain regions as well as in the spinal cord and myenteric plexus. Increased outward movement of K+ is the most likely mechanism for the postsynaptic hyperpolarisation and inhibition of neurons induced by opioids throughout the nervous system. However, it remains to be definitively established that this mechanism is also involved in the presynaptic action of opioids to inhibit neurotransmitter release.

Inhibition of adenylate cyclase
Adenylate cyclase is an enzyme that breaks down adenosine triphosphate (ATP) to form cyclic adenosine monophosphate (cAMP). All 3 types of opioid receptors couple to adenylate cyclase. Inhibition of adenylate cyclase may result in inhibition of neurotransmitter release.

Tolerance and dependence
Tolerance and dependence are induced by chronic exposure to morphine and other opioids more than any other group of drugs. Tolerance means that higher doses of opioids are required to produce an effect. When the degree of tolerance is very marked, the maximum response attainable with the opioid is also reduced. Tolerance is mainly due to receptor desensitisation induced by functional uncoupling of opioid receptors from G-proteins, thus uncoupling the receptors from their effector systems. However, the mechanism of this desensitisation is still not fully understood.

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.

Inhibition of neurotransmitter release is considered to be the major mechanism of action responsible for the clinical effects of opioids. Nevertheless, despite extensive investigation, understanding of the cellular actions of morphine and other opioids is incomplete. This is surprising for a group of drugs with such powerful effects, and is a reflection of the complexity of the mechanisms involved in neurotransmitter release. Confirmation of current hypotheses regarding mechanisms of opioid inhibition of neurotransmitter release must await the application of more refined techniques. Recent advances in the molecular biology of opioid receptors promise significant advances in opioid pharmacology and should aid discovery of opioids with more selective actions.

Further reading
Akil H, Simon EJ, editors. Opioids I and II. Handbook of experimental pharmacology. Berlin: Springer-Verlag, 1993; vol. 104.

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.

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