Basic Neurobiology of Addiction
Opioid peptides – β-endorphin, enkephalin, and dynorphin – are the endogenous ligands that naturally exist in the body and activate opioid receptors. Both opiate and opioid drugs bind to the same opioid receptor. An opiate is an alkaloid that resembles morphine and is derived from the opium poppy. An opioid is any drug (whether synthetic, semisynthetic, or endogenous) that binds to opioid receptors and has morphine-like effects. There are three types of opioid receptors: μ (mu), δ (delta), and κ (kappa).
Opioids have profound analgesic effects and rewarding properties. As such, they have both high medical use potential and high abuse potential. The analgesic effects of opioids are mediated by all three types of receptors. Their rewarding effects and dependence and addiction liability, however, are all largely mediated by the μ receptor.
Figure 2.12 Norepinephrine localization. Origin and distribution of central noradrenergic pathways in the rat brain. PFC, prefrontal cortex; Sept, septum; NAc, nucleus accumbens; MFB, medial forebrain bundle; Hypo, hypothalamus; DNAB, dorsal noradrenergic ascending bundle; VNAB, ventral noradrenergic ascending bundle; CTT, central tegmental tract. [Modified with permission from Robbins TW, Everitt BJ. Central norepinephrine neurons and behavior. In: Bloom FE, Kupfer DJ (eds.) Psychopharmacology: The Fourth Generation of Progress. New York, Raven Press, 1995, pp. 363–372.]
β-endorphin, the endogenous ligand for μ opioid receptors, is largely derived from proopiomelanocortin cells in the arcuate nucleus in the brain. It is distributed throughout the brainstem and basal forebrain and released from corticotropes in the anterior lobe of the pituitary.
Methionine and leucine enkephalins are endogenous ligands for δ opioid receptors. They are derived from the proenkephalin gene and have a widespread distribution in the basal forebrain, including the basal ganglia and midbrain, such as the periaqueductal gray.
Dynorphins can bind to all three opioid receptor subtypes but show a preference for κ receptors. They are derived from the prodynorphin precursor and contain the leucine (leu)-enkephalin sequence at the N-terminal portion of the molecule. Dynorphins are widely distributed in the central nervous system and play important roles in neuroendocrine regulation, pain regulation, motor activity, cardiovascular function, respiration, temperature regulation, feeding behavior, and stress responsivity. Dynorphin cell bodies and axon terminals are heavily localized to the central nucleus of the amygdala, bed nucleus of the stria terminalis, and nucleus accumbens shell (Figure 2.13). Activation of the dynorphin-κ receptor system produces actions that are similar to other opioids, such as analgesia, but the actions are often opposite to those of μ opioid receptors in the motivational domain. For example, μ agonists cause euphoria-like effects, and κ agonists produce dysphoric-like effects in animals and humans. Some evidence suggests that they also mediate negative emotional states. As a link between dopaminergic and opioidergic systems, dopamine D1 receptor activation in the nucleus accumbens shell can phosphorylate (turn on) cyclic adenosine monophosphate response element binding protein (CREB) and subsequently alter gene expression, notably the transcription of protachykinin and prodynorphin. Such activation of dynorphin systems has been suggested to contribute to the dysphoric-like syndrome associated with cocaine dependence and feedback to decrease dopamine release. Such enhanced dynorphin action may also drive corticotropin-releasing factor (a key neurotransmitter in the stress system) responses or be driven by activation of this stress hormone.