Opioid: A naturally occurring, semi-synthetic or synthetic agent that binds specifically to endogenous opioid receptors.
Agonist: A compound that binds to a receptor (has affinity), and produces a response at that receptor (intrinsic activity).
Partial agonist: A compound that has receptor affinity, but does not produce a full receptor response (submaximal intrinsic activity).
Antagonist: A compound that has receptor affinity, but does not produce a functional response (no intrinsic activity). While occupying receptor sites, antagonists prevent agonists from binding to the receptor.
Opioid receptor classification
Morphine and other opioid agents act on an endogenous system of opioid receptors. This system plays a vital role in the transmission and processing of painful stimuli, as well as the modulation of other systems such as gastrointestinal, autonomic, immune and endocrine functions.
The opioid system contains four opioid receptor types. These have been classified by the International Union of Pharmacology (IUPHAR) as:
- DOP (delta-) (previously OP1)
- KOP (kappa-) (previously OP2)
- MOP (mu-) (previously OP3)
- NOP (nociceptin/orphanin FQ) (previously OP4)
DOP, KOP and MOP receptors are considered to be classical opioid receptors, based on their sensitivity to the antagonist naloxone.
NOP receptors are a fairly recent discovery. They are morphologically similar to the classical opioid receptors, but exhibit different clinical effects and are not sensitive to naloxone. This has led to NOP receptors being considered as a ‘non-opioid branch of the opioid receptor family’ by IUPHAR.
Opioid receptors are distributed throughout the central nervous system, in both the ascending and descending pain pathways. Within the brain, they are found in high concentrations in the cerebral cortex, thalamus, locus coeruleus and periaqueductal grey matter of the midbrain. In the spinal cord, they are found in the substantia gelatinosa of the dorsal horn. They are also located on peripheral afferent nerves (A-delta fibres, C fibres and sympathetic nerves).
Additionally, opioid receptors are found in the gastrointestinal, cardiovascular, endocrine and immune systems.
Receptor morphology and action
Opioid receptors are selective inhibitory G protein-coupled receptors. Structurally, they consist of the typical seven transmembrane protein domains.
- Stimulation of the receptor results in a cascade of inhibitory intracellular events, including:
- Closing of voltage-sensitive calcium channels. This inhibits the release of neurotransmitters (substance P and glutamate) which play a role in transmission of pain impulses.
- Stimulation of potassium efflux leading to membrane hyperpolarisation and, therefore, inhibition of post-synaptic neurones.
- Inhibition of adenylyl cyclase, leading to reduced cyclic adenosine monophosphate (cAMP) production.
Overall, this results in reduced neuronal excitability and nociceptive transmission.
All opioid receptors have selective endogenous peptides, with varying degrees of potency and receptor affinity. These ligands are found throughout the nervous system, and in immune cells and neuroendocrine tissues. Endogenous opioids include compounds such as endorphins, encephalins, dynorphin and endomorphins. Although they do not currently have any clinical role, they have numerous physiological actions, including pain modulation and endogenous responses to shock.
The known clinically relevant opioids work via the activation of MOP receptors, although some are also active at other opioid receptors. For example, morphine also has some action at DOP and KOP receptors; oxycodone works at both MOP and KOP receptors; and buprenorphine (a partial opiate agonist) has varying activity at all four receptor types. At present, there are no specific targets for DOP, KOP or NOP receptors.
Pure opioid agonists, such as morphine, pethidine and fentanyl, bind to MOP receptors and demonstrate high intrinsic activity. Partial agonists, such as buprenorphine and pentazocine, have receptor affinity, but produce a lesser clinical effect. Opioid antagonists, such as naloxone and naltrexone, bind to DOP, KOP and MOP receptors, but have no intrinsic activity. They have no effect on NOP receptors.
Chronic exposure to opioid agents results in adaptions within opioid receptors, such as downregulation, receptor internalisation, uncoupling of receptors from G inhibitory proteins and increased production of nitric oxide. These adaptations may lead to withdrawal symptoms if the agents are stopped abruptly, and cause the development of tolerance and opioid-induced hyperalgesia.
The clinical effects elicited at opioid receptors depend on their type, morphology and location. These effects are summarised in Table 1.
Table 1. Clinical effects associated with opioid receptors.
|| Clinical effect|
- Spinal analgesia
- Respiratory depression
- Reduced gastric motility
- Spinal analgesia
- Diuresis (inhibition of antidiuretic hormone release)
- Supraspinal and spinal analgesia
- Respiratory depression
- Reduced gastrointestinal motility
- Endocrine effects – suppression of hypothalamic and pituitary hormone secretion
- Immunological effects
- Hyperalgesia at low doses, analgesia at high doses
1. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care (3rd edition). 2008. Cambridge University Press (pp 136–7).
2. McDonald J, Lambert DG. Opioid receptors. Continuing Education in Anaesthesia, Critical Care & Pain 2015; 15: 219–24.
3. Williams J. Basic opioid pharmacology. Reviews in Pain 2008; 1: 2–5.
4. Cross ME, Plunkett VE. Physics, Pharmacology and Physiology for Anaesthetists (2nd edition. 2014. Cambridge University Press) (pp 164–6).