Nervous system: Opioid receptors and naloxone

Opioids are a group of analgesic agents commonly used in pain management. There are three classical opioid receptors (DOR, KOR and MOR) – all of which are G-protein coupled receptors. Opioids can act on these receptors as agonists, antagonists or partial agonists. Opioid agonists cause cellular hyperpolarization upon binding to their receptors. Most clinically relevant opioid analgesics bind to MORs in the central and peripheral nervous system in an agonistic manner to elicit analgesia.

G-protein coupled receptors are composed of a transmembrane portion, which includes seven helices, and an intracellular portion, which consists of three subunits (α, β and γ). All of the opioid G-protein coupled receptors display similar cellular responses following receptor activation. The binding of an opioid agonist to the transmembrane portion of the receptor causes the α subunit of the G-protein to exchange its bound guanosine diphosphate (GDP) molecule with intracellular guanosine triphosphate (GTP). This then allows the α–GTP complex to dissociate from the βγ complex. The free complexes (α–GTP and βγ) interact with ion channels - usually inducing activation of potassium conductance and inhibition of calcium conductance - as well as intracellular proteins, inducing signaling outcomes as shown in Figure 1.

Figure 1 Cellular effects of opioid receptor activation, adapted from Pathan article cited below

When taken in large quantities, opioid medications, such as morphine, methadone, and fentanyl, can cause life-threatening symptoms, such as respiratory depression and reduced heart rate. Naloxone is an opioid antagonist that rapidly replaces drugs bound to opioid receptors, rapidly reversing symptoms of opioid toxicity. Figure 2 shows the relationship between dose and opioid receptor blockade 55 minutes after intravenous naloxone administration, and Figure 3 shows the relationship between opioid receptor blockade and time following administration of different doses of naloxone.

Figure 2 Percentage of opioid receptor blockade versus dose of IV naloxone (mg/kg) at t = 55 m post administration

Figure 3 Percentage of opioid receptor blockade versus time at different doses of naloxone

Sources: Pathan H, Williams J. Basic opioid pharmacology: an update. Br J Pain. 2012 Feb;6(1):11-6. doi: 10.1177/2049463712438493. PMID: 26516461; PMCID: PMC4590096. and Trøstheim, M., Eikemo, M., Haaker, J. et al. Opioid antagonism in humans: a primer on optimal dose and timing for central mu-opioid receptor blockade. Neuropsychopharmacol. 48, 299–307 (2023).