Opioid pharmacology: receptors, tolerance and opioid use disorder
How the body's own opioids and opioid drugs work, why the effect fades with time, and how opioid use disorder is treated.
Opioids act on a small family of G protein-coupled receptors that the body normally uses for its own pain-control peptides. The same receptors explain pain relief, euphoria, breathing depression, tolerance and dependence. This page connects the receptor biology with practical ideas: choice of route, switching opioids, opioid-induced hyperalgesia and the treatment of opioid use disorder.
Receptors and the body's own opioids
The classical opioid receptors are mu, delta and kappa. All couple to inhibitory Gi/o proteins: they lower cAMP, open potassium channels and close voltage-gated calcium channels, so neurons fire less and release less transmitter. The mu receptor is the main target of morphine, fentanyl, oxycodone and methadone, and of the body's beta-endorphin and enkephalins. Its activation relieves pain, produces pleasure and raises dopamine release in reward circuits, which links analgesia with misuse.
- Enkephalins: short peptides from proenkephalin; prefer delta over mu.
- Beta-endorphin: from proopiomelanocortin (POMC); prefers mu.
- Dynorphins: from prodynorphin; natural kappa ligands, linked to dysphoria.
- Nociceptin (orphanin FQ): acts at the NOP receptor, which opioid drugs and the classic peptides do not activate.
Tolerance, dependence and opioid-induced hyperalgesia
With repeated dosing, the same dose gives less effect (tolerance). Short-term tolerance involves receptor phosphorylation, uncoupling from G proteins and internalisation, but these changes alone do not explain long-lasting tolerance; adaptive changes in signalling and circuits follow. Physical dependence shows up as withdrawal (agitation, diarrhoea, pupil dilation, raised heart rate, more pain) when the drug stops or an antagonist is given. Chronic opioid exposure can also enhance NMDA glutamate receptor activity, a mechanism proposed for opioid-induced hyperalgesia: pain that worsens despite higher doses, eases when the dose is lowered, or spreads to normally non-painful stimuli. The US label for every opioid analgesic now warns about it, and the suggested response is a lower dose or a switch to another opioid, not escalation.
Routes and opioid rotation
Opioids can be given orally, intravenously, subcutaneously, rectally, by transdermal patch (lipid-soluble drugs such as fentanyl and buprenorphine) and by epidural or intrathecal injection, where small amounts act directly on the spinal cord. Oral immediate-release forms are the usual choice for short-term acute pain; extended-release and long-acting forms are reserved for severe, persistent pain where alternatives are inadequate. Because cross-tolerance between mu agonists is incomplete, switching to a different opioid (rotation) can restore analgesia or reduce side effects; the new drug is started cautiously, since the patient may be more sensitive to it than expected.
Combination and multimodal analgesia
Opioids work best as one part of a plan. Non-opioid analgesics (paracetamol, NSAIDs), regional anaesthesia and non-drug treatments allow lower opioid exposure. Combining opioids with benzodiazepines or other CNS depressants raises the risk of fatal breathing depression, so these combinations call for caution and for offering naloxone.
Opioid use disorder and harm reduction
Opioid use disorder is a chronic, treatable condition. Medication is the core of treatment and is often combined with counselling and social support.
- Methadone: a full mu agonist with a slow onset and long action; it reduces craving and withdrawal.
- Buprenorphine: a partial mu agonist that also blocks other opioids; some products add naloxone. It can be started in the emergency department after an overdose.
- Naltrexone: an antagonist; it requires that other opioids have been stopped first.
- Lofexidine: an alpha-2 agonist that eases acute withdrawal but is not long-term treatment.
- Harm reduction: naloxone for overdose reversal, and treatment that lowers risky injection behaviours linked to HIV and hepatitis C.
Why the agonist medicines matter
People treated with methadone or buprenorphine are less likely to overdose or die than untreated people, and both help them stay in treatment. Yet only a minority of people with opioid use disorder receive these medicines. The FDA advises that naloxone be discussed with everyone prescribed an opioid and considered for those at higher risk, such as people also using benzodiazepines or with a past overdose.
Test yourself
Think of the answer, then tap the question to see it.
Which endogenous opioid peptides are the natural ligands of the kappa receptor?
The dynorphins, which come from the precursor prodynorphin.
What is the pharmacological basis of opioid rotation?
Cross-tolerance between mu agonists is incomplete, so a different opioid may relieve pain better or with fewer side effects after tolerance to the first one.
How does opioid-induced hyperalgesia differ from tolerance?
In tolerance the same dose gives less relief; in hyperalgesia the opioid itself increases pain or pain sensitivity, and pain may improve when the dose is lowered.
Why can buprenorphine block the effect of other opioids?
It is a partial mu agonist that binds the receptor tightly, so it occupies the site while activating it less than full agonists.
Example drugs
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: OPRM1 gene: MedlinePlus Genetics (MedlinePlus (U.S. National Library of Medicine), 2026); FDA updates prescribing information for all opioid pain medicines to provide additional guidance for safe use (U.S. Food and Drug Administration, 2026); Medications for Opioid Use Disorder (National Institute on Drug Abuse (NIDA), 2026).
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Representative model, for educational purposes only.