Opioids - Drugs That Activate Gio-Coupled Receptors

DRUGS THAT ACTIVATE G_IO-COUPLED RECEPTORS

OPIOIDS

Opioids may have been the first drugs to be abused (preceding stimulants), and are still among the most commonly used for nonmedical purposes.

Pharmacology & Clinical Aspects

As described, opioids comprise a large family of endogenous and exogenous agonists at three G protein-coupled receptors: the μ-, κ-, and δ-opioid receptors. Although all three receptors couple to inhibitory G proteins (ie, they all inhibit ade-nylyl cyclase), they have distinct, sometimes even opposing effects, mainly because of the cell type-specific expression throughout the brain. In the VTA, for example, μ-opioid receptors are selectively expressed on GABA neurons (which they inhibit), whereas κ-opioid receptors are expressed on and inhibit dopamine neu-rons. This may explain why μ-opioid agonists cause euphoria, whereas κ agonists induce dysphoria.

In line with the latter observations, the rewarding effects of morphine are absent in knockout mice lacking μ receptors but persist when either of the other opioid receptors are ablated. In the VTA, μ opioids cause an inhibition of GABAergic inhibitory interneurons, which leads eventually to a disinhibition of dop-amine neurons.

The most commonly abused μ opioids include morphine,heroin (diacetylmorphine, which is rapidly metabolized to mor-phine), codeine, and oxycodone. Meperidine abuse is common among health professionals. All of these drugs induce strong toler-ance and dependence. The withdrawal syndrome may be very severe (except for codeine) and includes intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, and fever. Beyond the withdrawal syndrome, which usually lasts no longer than a few days, individuals who have received opioids as analgesics only rarely develop addiction. In contrast, when taken for recreational pur-poses, opioids are highly addictive. The relative risk of addiction is 4 out of 5 on a scale of 1 = nonaddictive, 5 = highly addictive.

Treatment

The opioid antagonist naloxone reverses the effects of a dose of morphine or heroin within minutes. This may be life-saving in the case of a massive overdose. Naloxone administration also provokes an acute withdrawal (precipitated abstinence) syndrome in a dependent person who has recently taken an opioid.

In the treatment of opioid addiction, a long-acting opioid (eg, methadone, buprenorphine) is often substituted for the shorter-acting, more rewarding, opioid (eg, heroin). For substitution therapy, methadone is given orally once daily, facilitating super-vised intake. Using a partial agonist (buprenorphine) and the much longer half-life (methadone and buprenorphine) may alsohave some beneficial effects (eg, weaker drug sensitization, which typically requires intermittent exposures), but it is important to realize that abrupt termination of methadone administration invariably precipitates a withdrawal syndrome; that is, the subject on substitution therapy remains dependent. Some countries (eg, Switzerland, Netherlands) even allow substitution of heroin by heroin. A follow-up of a cohort of addicts who receive heroin injections in a controlled setting and have access to counseling indicates that addicts under heroin substitution have an improved health status and are better integrated in society.