Naloxone

Naloxone is a drug that acts as an opiate antagonist. It has a high affinity for the receptors that serve the body's endogenous opiates, or exogenous drugs like morphine or heroin.

Endogenous opioid systems

The endogenous opioid systems comprise three major families: the enkephalins, leu-enkephalin and met-enkephalin; the endorphins, particularly beta-endorphin, and the dynorphins; these families are encoded by separate genes that code for large precursor molecules (pro-opiomelanocortin (POMC); proenkephalin and prodynorphin respectively) which are cleaved enzymatically to produce the relevant active opioid peptide. These endogenous opioids act at three large classes of G-protein coupled receptors - the mu receptor (at which morphine binds with very high affinity; the delta receptor (at which leu-enkephalin is the endogenous ligand) and the kappa receptor (at which dynorphins bind with high affinity). POMC is produced only by subpopulations of neurones in the arcuate nucleus and caudal brainstem; dynorphin is expressed by many populations including the vasopressin cells of the supraoptic nucleus and paraventricular nucleus and by neurones in the arcuate nucleus. Enkephalins are produced by many neuronal populations. Leu-enkephalin can also be produced by cleavage of prodynorphin. These "systems" play many different physiological roles; there is not one opioid system in the body, or even three, but many: opioids play a different role in each neuronal population where they are expressed.

Affinity and selectivity

Naloxone binds to mu receptors with very high affinity but is less potent at kappa receptors and still less potent at delta receptors; it is thus (at low doses) a relatively selective mu antagonist. Naloxone is soluble in aqueous solutions, and penetrates the blood-brain barrier freely, so its high affinity at mu receptors make it an important tool for studying the role of endogenous opiod systems.

Use in morphine withdrawal

Interest in the addictive properties of opiates has stimulated research into naloxone, which has been associated with immediate withdrawal symptoms in users of heroin. Naloxone may counter the behavioral suppression of opiates (e.g. the euphoria and lethargy following morphine injection) by its competition with opiates at mu receptors. It is also possible that naloxone itself exerts some behavioral influence, either in the form of general activity enhancement or as a suppressor of behavior. Experiments with the hamster suggest that naloxone injected before morphine can drive activity levels even above those of saline controls. But other research on naloxone has shown that it, like morphine, may suppress some behaviors, e.g. sexual behavior in male rats. In some sases, for naloxone to depress activity it appears to be necessary that it be injected at relatively high doses (e.g. 10 mg/kg and above in rats), indicating that, in such cases, its effects are not exerted at mu receptors but probably at kappa receptors. .