ATrain Education

 

Continuing Education for Health Professionals

Opioids as Medications

Module 2

Opioids and Their Receptors

Opioids are chemicals that produce morphine-like effects in the body; these effects are blocked by antagonists of morphine such as naloxone. Agonists for opioid receptors include various neuropeptides (beta-endorphin, dynorphins, enkephalins, endomorphin) and other synthetic compounds that may have very different chemical structures than morphine. Opiates are a subset of opioids and are naturally occurring molecules that have very similar chemical structure to morphine and would therefore not include the neuropeptides.

Early studies with opioids implied that there must be multiple types of target receptors in the human body because different opioid compounds produced varied levels of effects including analgesia, respiratory depression, pupillary constriction, bradycardia (slow heart rate), reduced gastrointestinal GI motility, smooth muscle spasm, euphoria, sedation, and physical dependence.

Opioid receptors are members of the G protein-coupled receptors (GPCRs) that act to inhibit adenylate cyclase and thereby reduce intracellular levels of cyclic adenosine monophosphate (cAMP). Opioids can also have more direct roles in opening potassium channels (preventing nerve hyperpolarization and synapse firing) and to inhibit voltage-gated calcium channels at the cell membrane. Both have the net effect of reducing the excitability of neurons and the release of transmitter calcium to signal other neurons.

Opioid receptors are found extensively in the brain and spinal cord, as well as in vascular, gut, lung airway, cardiac, and some immune system cells.

Mu, Delta, and Kappa Receptors

There are three family members of opioid receptors, with similar protein sequences and structures (Kane et al., 2006). They are all transmembrane proteins of the rhodopsin family of GPCRs, embedded in the cell membrane and crossing it seven times. The Mu opioid receptors (MOR) are thought to give most of their analgesic effects in the central nervous system, as well as many side effects including sedation, respiratory depression, euphoria, and dependence. Most analgesic opioids are agonists on MOR (see table below). The Delta opioid receptors (DOR) are more prevalent for analgesia in the peripheral nervous system. The Kappa opioid receptors (KOR) contribute to analgesia in the spine and may exhibit dysphoria and sedation, but do not generally lead to dependence. Some drugs are relatively KOR-specific (Brunton et al., 2011).

 

Key: + is agonist, – is antagonist.
Source: Adapted from Goodman and Gilman, 2011, and Molecular Pharmacology, 2000.

Selectivity of Opioids for Opioid Receptors

Opioid ligands

Opioid receptor types

Opioid ligands

Mu (MOR)

Delta (DOR)

Kappa (KOR)

Agonists

Morphine

+++

+

++

Codeine

+

+

+

Meperidine

++

+

+

Hydromorphone

+++

 

+

Etorphine

+++

+++

+++

Methadone

+++

 

 

Fentanyl

+++

+

 

Sufentanil

+++

+

 

Partial mixed agonists

Pentazocine

+

++

Nalbuphine

– – –

+

++

Buprenorphine

+

 

– –

Antagonists

Naloxone

– – –

– –

Naltrexone

– – –

– – –

Neuropeptides

Beta-endorphin

+++

+++

 

Dynorphin

++

+

+++

Enkephalins

++

+++

 

Endomorphin

+++

 

 

 

At the cellular level, all three receptor types act similarly, though their distribution in the body and sensitivity to various opioid drugs lead to markedly different pharmacologic reactions. In addition, all three of these subtypes are present in some tissues at various levels, further modulating the responses. In the membrane, opiate receptors can form both homo- and heterodimers, altering the pharmacologic properties of the respective receptors. For example, DORs can form heterodimers with both KORs and MORs. Thus, MOR-DOR and DOR-KOR heterodimers show less affinity for highly selective agonists and reduced receptor recycling.

Agonists and Antagonists

Opioids can be classified as agonists (activators), antagonists (blockers), or partial agonist/ antagonists on their target receptors. Some opioids act as full agonists on one type of receptor and may be partial or antagonists on another subtype, complicating the pharmacologic responses to a drug (Molecular Pharmacology, 2000). One group of compounds consists of pure agonists, including many of the most common morphine-like drugs. They have high affinity for the mu receptors and varying affinities for the kappa and delta receptors. Some of these (eg, methadone, codeine, dextropropoxyphene) are weak agonists—their maximal pain relief and side effects are much less than those of morphine and they usually do not lead to addiction.

Partial agonists have mixed agonist-antagonist character; for example, nalorphine and pentazocine have a degree of agonism or antagonism on different receptors. Nalorphine can be an agonist in some tissues, yet competitively block the otherwise stronger effects of morphine there. Pentazocine and nalbuphine are antagonists on mu receptors but are partial agonists on KOR and DOR. This class of drugs usually results in dysphoria (emotional state marked by anxiety, depression, and restlessness) rather than euphoria.

Antagonists, including naloxone and naltrexone, have little effect if given on their own but are very effective inhibitors of the actions of other opioids, because they block the binding sites for agonists on the receptors.

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