[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Pharmacology](https://durgical.com/en/pharmacology/) › Opioid pharmacology: receptors, tolerance and opioid use disorder # 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. Updated Nov 12, 2026 On this page - The basics Key points - Receptors and the body's own opioids - Tolerance, dependence and opioid-induced hyperalgesia - Routes and opioid rotation - Combination and multimodal analgesia - Opioid use disorder and harm reduction - Why the agonist medicines matter - Memory aid - Example drugs - Study Test yourself - Connections Connections 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. ## Key points - Three families of endogenous opioid peptides act at the classical receptors: enkephalins, endorphins (mainly beta-endorphin) and dynorphins. - Beta-endorphin prefers the mu receptor and the dynorphins are the natural ligands of the kappa receptor; nociceptin acts on a related receptor (NOP) that opioid drugs do not bind. - Cross-tolerance between mu agonists is real but incomplete, which is the basis for opioid rotation. - Opioid-induced hyperalgesia is a paradoxical rise in pain or pain sensitivity on opioids; it is distinct from tolerance and withdrawal. - Methadone and buprenorphine reduce overdose and death in opioid use disorder; naloxone reverses overdose. ## 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. ## Memory aid «MEK» for the body's opioids: Mu likes beta-Endorphin, Enkephalins lean Delta, Kappa keeps the dynorphins. ## 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. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/pharmacology/topics/opioid-pharmacology-receptors-tolerance-and-opioid-use-disorder/) [More Pharmacology questions →](https://durgical.com/en/practice/?f=pharmacology) ## Example drugs - [Morphine](https://durgical.com/en/pharmacology/morphine/) - [Fentanyl](https://durgical.com/en/pharmacology/fentanyl/) - [Oxycodone](https://durgical.com/en/pharmacology/oxycodone/) - [Methadone](https://durgical.com/en/pharmacology/methadone/) - [Buprenorphine](https://durgical.com/en/pharmacology/buprenorphine/) - [Naloxone](https://durgical.com/en/pharmacology/naloxone/) - [Naltrexone](https://durgical.com/en/pharmacology/naltrexone/) - [Lofexidine](https://durgical.com/en/pharmacology/lofexidine/) ## Connections ## Related classes 2 - [Opioids and antagonists](https://durgical.com/en/pharmacology/classes/opioids-and-antagonists/) - [Medicines for alcohol use disorder](https://durgical.com/en/pharmacology/classes/medicines-for-alcohol-use-disorder/) [← All of pharmacology](https://durgical.com/en/pharmacology/) 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](https://medlineplus.gov/genetics/gene/oprm1/) (MedlinePlus (U.S. National Library of Medicine), 2026); [FDA updates prescribing information for all opioid pain medicines to provide additional guidance for safe use](https://www.fda.gov/drugs/drug-safety-communications/fda-updates-prescribing-information-all-opioid-pain-medicines-provide-additional-guidance-safe-use) (U.S. Food and Drug Administration, 2026); [Medications for Opioid Use Disorder](https://nida.nih.gov/publications/research-reports/medications-to-treat-opioid-addiction/overview) (National Institute on Drug Abuse (NIDA), 2026). ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/pharmacology/topics/opioid-pharmacology-receptors-tolerance-and-opioid-use-disorder/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/pharmacology/topics/opioid-pharmacology-receptors-tolerance-and-opioid-use-disorder/