Basic Neurobiology of Addiction

Nociceptin

Nociceptin (also known as orphanin FQ) is a 17-amino-acid polypeptide that is structurally related to the opioid peptide dynorphin A. It is the endogenous ligand for the nociceptin opioid (NOP) receptor (formerly referred to as opioid receptor-like-1). Nociceptin does not bind to μ, δ, or κ opioid receptors, and no known exogenous or endogenous opioids bind to the NOP receptor. The neuroanatomical distribution of nociceptin and its receptor are distinct from other opioid peptides. The highest density of nociceptin and the NOP receptor is in the cortex, amygdala, bed nucleus of the stria terminalis, medial prefrontal cortex, ventral tegmental area, lateral hypothalamus, nucleus accumbens, and many brainstem areas, including the locus coeruleus and raphe (Figure 2.17).

NOP receptor agonists and antagonists have numerous functional effects that are related to anxiety-like and stress-like states. Nociceptin blocks stress-induced analgesia triggered by the release of endogenous opioids. Nociceptin generally attenuates adaptive behaviors to stress, such as opioid and non-opioid stress-induced analgesia and stress-induced anorexia. Nociceptin and small-molecule synthetic nociceptin analogs have a broad anxiolytic-like profile in animals and also reverse stress-induced anorexia. Nociceptin may play a role in the addiction process that is independent of any classic opioid action. Nociceptin and synthetic NOP receptor agonists decrease the acute rewarding effects of drugs of abuse in the conditioned place preference paradigm. They also block alcohol consumption in a genetically selected line of rats that is known to be hypersensitive to stressors and decrease reinstatement of drug seeking behavior.

Figure 2.17 Nociceptin/orphanin FQ localization. Schematic representation of the distribution of nociceptin peptide in the rat central nervous system determined by immunohistochemistry and in situ hybridization. Neuronal perikarya are shown as solid circles, and fiber-terminals are shown as short curved lines and dots. AA, anterior amygdala; ABL, basolateral nucleus of amygdala; AC, anterior commissure; ACB, nucleus accumbens; ACE, central nucleus of the amygdala; ACO, cortical nucleus of amygdala; AD, anterodorsal nucleus of thalamus; AL, anterior lobe of pituitary; AM, anteromedial nucleus of thalamus; AMB, nucleus ambiguus; AME, medial nucleus of the amygdala; AON, anterior olfactory nucleus; ARC, arcuate nucleus; AV, anteroventral nucleus of thalamus; BST, bed nucleus of the stria terminalis; CC, corpus callosum; CGX, cingulate cortex; CM, central-medial nucleus of thalamus; COCH, cochlear nuclear complex; CPU, caudate-putamen; CST, corticospinal tract; DH, dorsal horn of spinal cord; DG, dentate gyrus; DM, dorsomedial nucleus of hypothalamus; DNV, dorsal motor nucleus of vagus; DTN, dorsal tegmental nucleus; ENT, entorhinal cortex; FN, fastigial nucleus of cerebellum; FRX, frontal cortex; GL, glomerular layer of olfactory bulb; GP, globus pallidus; HM, medial habenular nucleus; HPC, hippocampus; IC, inferior colliculus; IL, intermediate lobe of pituitary; IP, interpeduncular nuclear complex; LC, nucleus locus coeruleus; LG, lateral geniculate nucleus; LHA, lateral hypothalamic area; LRN, lateral reticular nucleus; MF, mossy fibers of hippocampus; MFN, motor facial nucleus; MG, medial geniculate nucleus; ML, medial lemniscus; MM, medial mammillary nucleus; MNT, mesencephalic nucleus of trigeminal; MVN, medial vestibular nucleus; NCU, nucleus cuneatus; NCX, neocortex; NDB, nucleus of diagonal band; NL, neural lobe of pituitary; NRGC, nucleus reticularis gigantocellularis; NRPG, nucleus reticularis paragigantocellularis; NTS, nucleus tractus solitarius; OCX, occipital cortex; OT, optic tract; OTU, olfactory tubercle; PAG, periaqueductal gray; PAX, periamygdaloid cortex; PBN, parabrachial nucleus; PC, posterior commissure; PIR, piriform cortex; PN, pons; POA, preoptic area; PP, perforant path; PV, periventricular nucleus of thalamus; PVN(M), paraventricular nucleus (pars magnocellularis); PVN(P), paraventricular nucleus (pars parvocellularis); RD, nucleus raphe dorsalis; RE, nucleus reuniens of thalamus; RF, reticular formation; RM, nucleus raphe magnus; RME, nucleus raphe medianus; SC, superior colliculus; SCP, superior cerebellar peduncle; SM, stria medullaris thalami; SNC, substantia nigra (pars compacta); SNR, substantia nigra (pars reticulata); SNT, sensory nucleus of trigeminal (main); SON, supraoptic nucleus; SPT, septal nuclei; STN, spinal nucleus of trigeminal; SUB, subiculum; VM, ventromedial nucleus of hypothalamus; VP, ventral pallidum; ZI, zona incerta. [Taken with permission from Koob GF. A role for brain stress systems in addiction. Neuron, 2008, (59), 11-34.]

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