Reward processing by the opioid system in the brain

Abstract

The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides processed from three protein precursors, proopiomelanocortin, proenkephalin, and prodynorphin. Opioid receptors are recruited in response to natural rewarding stimuli and drugs of abuse, and both endogenous opioids and their receptors are modified as addiction develops. Mechanisms whereby aberrant activation and modifications of the opioid system contribute to drug craving and relapse remain to be clarified. This review summarizes our present knowledge on brain sites where the endogenous opioid system controls hedonic responses and is modified in response to drugs of abuse in the rodent brain. We review 1) the latest data on the anatomy of the opioid system, 2) the consequences of local intracerebral pharmacological manipulation of the opioid system on reinforced behaviors, 3) the consequences of gene knockout on reinforced behaviors and drug dependence, and 4) the consequences of chronic exposure to drugs of abuse on expression levels of opioid system genes. Future studies will establish key molecular actors of the system and neural sites where opioid peptides and receptors contribute to the onset of addictive disorders. Combined with data from human and nonhuman primate (not reviewed here), research in this extremely active field has implications both for our understanding of the biology of addiction and for therapeutic interventions to treat the disorder.

Figures

Fig. 1

Anatomical distribution of opioid receptors (A) and peptides (B) in the rodent brain (rat and mouse). Only brain regions for which data are available in the literature are represented. Colors correspond to each of the three opioid receptor or peptide precursor. Densities are represented by symbols of different sizes, from low to high. A: receptors. Top panel represents the distribution of opioid receptor proteins as determined by ligand autoradiography. Maximal Bmax (receptor densities, radiolabeled ligands) values reported in the literature for mu and delta receptors were ~170–200 fmol/mg tissue equivalent (IP and olfactory bulbs, respectively). Maximal Bmax values recorded for kappa receptors were 80–100 fmol/mg (Cl; Refs. 144, 193, 346). Bottom panel summarizes the localization of cell bodies expressing opioid receptors based on the detection of mRNAs by in situ hybridization. B: peptides. Top panel depicts the pattern of distribution of opioid peptides by immunohistochemistry. Bottom panel maps cell bodies expressing opioid peptides, as evaluated both by immunohistochemical and in situ hybridization studies. Note: for immunohistochemical mapping, data based on antibodies for peptide precursors were used in priority. When not available, data based on antibodies for final peptides were used, with priority given to peptides issued from a single precursor (β-endorphin and dynorphin). Refer to text for further comments. Amb, nucleus ambiguus; AD, anterodorsal thalamus; AL, anterior lobe, pituitary; AON, anterior olfactory nucleus; Arc, arcuate nucleus, hypothalamus; BLA, basolateral nucleus, amygdala; BNST, bed nucleus of the stria terminalis; CeA, central nucleus, amygdala; Cl, claustrum; CL, centrolateral thalamus; CM, centromedial thalamus; CoA, cortical nucleus, amygdala; CPu, caudate putamen; CrbN, cerebellar nuclei; DMH, dorsomedial hypothalamus; DMR, dorsal and medial raphé; DTN, dorsal tegmental nucleus; En, endopiriform cortex; Ent, entorhinal cortex; FrCx, frontal cortex; G, nucleus gelatinosus, thalamus; G/VP, globus pallidus/ventral pallidum; HbL, lateral habenula; HbM, medial habenula; HPC, hippocampus; IL, intermediate lobe, pituitary; IP, interpeduncular nucleus; LC, locus coeruleus; LD, laterodorsal thalamus; LG, lateral geniculate, thalamus; LH, lateral hypothalamus; LRN, lateral reticular nucleus; MD, mediodorsal thalamus; Me, median eminence; MEA, median nucleus, amygdala; MG, medial geniculate; MM, medial mammillary nucleus; MV, medial vestibular nucleus; NAc, nucleus accumbens; NL, neuronal lobe, pituitary; NRGC, nucleus reticularis gigantocellularis; NTS, nucleus tractus solitarius; OCx, occipital cortex; PAG, periaqueductal gray; PCx, parietal cortex; Pir, piriform cortex; PN, pontine nucleus; PnR, pontine reticular; PO, posterior thalamus; POA, preoptic area; PPTg, pedunculopontine nucleus; PrS, presubiculum; PV, paraventricular thalamus; PVN, paraventricular hypothalamus; RE, reuniens thalamus; RN, red nucleus; RM, raphé magnus; SON, supraoptic nucleus; SN, substancia nigra; SNT, sensory trigeminal nucleus; STN, spinal trigeminal nucleus; TCx, temporal cortex; Th, thalamus; Tu, olfactory tubercle; Tz, trapezoid nucleus; VL, ventrolateral thalamus; VM, ventromedial thalamus; VMH, ventromedial hypothalamus; VPL, ventroposterolateral thalamus; VTA, ventral tegmental area; ZI, zona incerta.

Fig. 2

Schematic representation of the brain reinforcement circuit. Brain sites of reinforcement are integrated in a circuit based on their connectivity and putative functional roles. BNST, bed nucleus of the stria terminalis; CPu, caudate putamen; LH, lateral hypothalamus; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; PAG, periaqueductal gray; POA, preoptic area; VP, ventral pallidum; VTA, ventral tegmental area. [Adapted from Kelley (183) and Koob and Le Moal (202).]

Fig. 3

Brain sites where opioid agonists or antagonists modulate food intake. A: brain sites where opioid receptor agonists injected locally either increase or decrease food intake. B: brain sites where microinjections of opioid receptor antagonists decrease feeding behavior. Food was either standard chow or palatable (energy-dense) diet. Food intake was either basal or induced by food deprivation, intracerebral electrical stimulation, or local pharmacological injection. Opioid agonists and antagonists modulate food intake mainly through regulation of hedonic evaluation, but also contribute to these behaviors by modulating integration of sensory processes or the regulation of energy needs. AMG, amygdala; Arc, arcuate nucleus, hypothalamus; CPu, caudate putamen; DMH, dorsomedial hypothalamus; LH, lateral hypothalamus; NAc, nucleus accumbens; NTS, nucleus tractus solitarius; PAG, periaqueductal gray; PBN, parabrachial nucleus; PVN, paraventricular hypothalamus; VP, ventral pallidum; VTA, ventral tegmental area.

Fig. 4

Brain sites where opioid agonists or antagonists modulate drug reinforcement. A: brain regions where injections of opioid agonists have direct positive or negative reinforcing properties. B: brain sites where microinjections of opioid antagonists inhibit the reinforcing effects of opioid drugs given systematically. C: brain areas where local injections of opioid antagonists decrease reinforcing properties of systemic nonopioid drugs (ethanol, cocaine, or nicotine). Reinforcement was assessed using animal models of drug-induced conditioned place preference or self-administration. Brain regions represented on this figure were reported to be sensitive to local opioid injections at least once in the literature. Conflicting results might have been reported in other studies, most often using a different animal model. Noteworthy, most brain areas where opioid manipulations impact on drug reinforcement express all three types of opioid receptors. Amb, nucleus ambiguus; AMG, amygdala; BNST, bed nucleus of the stria terminalis; CPu, caudate putamen; dRF, dorsal reticular formation; HPC, hippocampus; LH, lateral hypothalamus; lTh, lateral thalamus; mPFC, medial prefrontal cortex; mTh, medial thalamus; NAc, nucleus accumbens; PBN, parabrachial nucleus; PAG, periaqueductal gray; POA, preoptic area; PPTg, pedunculopontine nucleus; R, red nucleus; SN, substancia nigra; VP, ventral pallidum; vRF, ventral reticular formation; VTA, ventral tegmental area; vTh, ventral thalamus.

Fig. 5

Regulation of opioid peptide genes after chronic exposure to, or withdrawal from, drugs of abuse. Each panel represents brain areas where modifications of endogenous opioid peptide transcript levels were described after chronic exposure to, or withdrawal from, morphine (A), ethanol (B), cannabinoid agonist (C), cocaine (D), and nicotine (E). Chronic drug administration (full arrows) corresponds to repeated injections (constant or escalating doses), pellets implantation, minipump infusions, or self-administration of the drug of abuse. Withdrawal (hatched arrows) was either spontaneous (cessation of injections or removal of pellets) or induced by antagonist injection. Many studies have also reported negative results (no detectable regulation) that are not represented on the figure but discussed in the text. AL, anterior lobe, pituitary; Arc, arcuate nucleus; CeA, central nucleus, amygdala; CPu, caudate putamen; Cx, cortex; FrCx, frontal cortex; HPC, hippocampus; HPT, hypothalamus; IL, intermediate lobe, pituitary; LH, lateral hypothalamus; MBH, medial basal hypothalamus; MM, medial mammillary nucleus; MO, medulla oblongata; NAc, nucleus accumbens; NL, neuronal lobe, pituitary; PAG, periaqueductal gray; PGi, nucleus paragigantocellularis; Pir, piriform cortex; PVN, paraventricular hypothalamus; SON, supraoptic nucleus; Tu, olfactory tubercle; VMH, ventromedial hypothalamus.