Tolerance to opioids may be due to a reduction of the concentration of a drug or a shorter duration of action in a target system (pharmacokinetic tolerance). Alternatively, it may involve changes of μ-opioid receptor function (pharmacodynamic tolerance). In fact, many μ-opioid receptor agonists promote strong receptor phosphorylation that triggers the recruitment of the adaptor protein β-arrestin, causing G proteins to uncouple from the receptor and to internalize within minutes (see Chapter 2). Since this decreases signaling, it is tempting to explain tolerance by such a mechanism. However, morphine, which strongly induces tolerance, does not recruit β-arrestins and fails to promote receptor internalization (see Chapter 31). Conversely, other agonists that
TABLE 32–1 The mechanistic classification of drugs of abuse.1 5-HTxR, serotonin receptor; CB1R, cannabinoid-1 receptor; DAT, dopamine transporter; GABA, γ-aminobutyric acid; Kir3 channels, G protein-coupled inwardly rectifying potassium channels; LSD, lysergic acid diethylamide; μ-OR, μ-opioid receptor; nAChR, nicotinic acetylcholine receptor; NET, norepinephrine transporter; NMDAR, N-methyl-D-aspartate receptor; R, receptor; SERT, serotonin transporter; VMAT, vesicular monoamine transporter; ? indicates data not available.
1Drugs fall into one of three categories, targeting either G protein-coupled receptors, ionotropic receptors or ion channels, or biogenic amine transporters.
2RR, relative risk of addiction; 1 = nonaddictive; 5 = highly addictive.
drive receptor internalization very efficiently induce only modest Adaptive changes become fully apparent once drug exposure tolerance. Based on these observations, it has been hypothesized is terminated. This state is called withdrawal and is observed to that desensitization and receptor internalization actually protect varying degrees after chronic exposure to most drugs of abuse. the cell from overstimulation. In this model, morphine, by fail-Withdrawal from opioids in humans is particularly strong ing to trigger receptor endocytosis, disproportionally stimulates (described below). Studies in rodents have added significantly to adaptive processes, which eventually cause tolerance. Although our understanding of the neural and molecular mechanisms that the molecular identity of these processes is still under investiga-underlie dependence. For example, signs of dependence, as well tion, they may be similar to the ones involved in withdrawal as analgesia and reward, are abolished in knockout mice lack(see below). ing the μ-opioid receptor, but not in mice lacking other opioid
Class 2 (benzodiazepines, nicotine, ethanol): channels Class 3 (cocaine, amphetamine, ecstasy): transporters (opioids, THC, GHB): GPCRs Glutamate GABA GABA DA Increased dopamine (all addictive drugs)
FIGURE 32–2 Neuropharmacologic classification of addictive drugs by primary target (see text and Table 32–1). DA, dopamine; GABA, γ-aminobutyric acid; GHB, γ-hydroxybutyric acid; GPCRs, G protein-coupled receptors; THC, Δ9-tetrahydrocannabinol.