Research ReportThe dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors
Introduction
Continuous exposure to stressful experience is well known to induce despair and escalate the risk of mood disorders and drug abuse (Gold and Chrousos, 2002, Volkow and Li, 2004, Koob and Kreek, 2007). Two major families of stress neuropeptides that mediate these processes are the corticotropin-releasing factor (CRF, also called corticotropin-releasing hormone, CRH) peptides and the dynorphins (Bale, 2005, Nestler and Carlezon, 2006). The existence of a CRF-like substance in hypothalamus was originally proposed in 1955, and CRF was isolated and sequenced by Vale et al. (1981). Contemporaneously, other groups including de Castiglione also identified CRF-related peptides sauvagine and urotensin alongside CRF in the early 1980s (Erspamer et al., 1980, Rivier et al., 1983). Urocortin was isolated and characterized in the mid 1990s (Vaughan et al., 1995), and found to have a sequence that was related to CRF peptides. CRF was first thought only to be critical for the regulation of endocrine stress physiology by regulation of the hypothalamic–pituitary axis (HPA) and subsequent adrenocorticosteroid release. Later in adrenalectomized animals, however, CRF and related neuropeptides were also demonstrated to maintain homeostasis in response to stressful stimuli in behavioral models suggesting that CRF may have other effects in addition to HPA activation (Veldhuis and De Wied, 1984), and CRF receptors are broadly distributed in brain (Bale and Vale, 2004).
At around the time that CRF was isolated, the endogenous opioid peptide dynorphin A was discovered by Goldstein et al., 1979, Goldstein et al., 1981. Soon afterwards, other forms of dynorphin (α-neo-endorphin, dynorphin A(1-8), and dynorphin B) were also described (Seizinger et al., 1981, Weber et al., 1981, Cone et al., 1983). The effects of the dynorphins were initially characterized in the peripheral nervous system including the guinea pig ileum longitudinal muscle–myenteric plexus and mouse vas deferens tissue bath preparations where opioid receptors strongly inhibit electrically evoked smooth muscle contraction (Chavkin and Goldstein, 1981, Cox and Chavkin, 1983). Dynorphin was later found to mediate antinociceptive responses (Herman and Goldstein, 1985, Spampinato and Candeletti, 1985). Dynorphin has also been demonstrated to inhibit vasopressin release to cause diuresis and reduce blood pressure (Leander, 1983, Grossman and Rees, 1983). In the central nervous system an extensive literature also described a role for dynorphin in the hippocampus (for review see Drake et al., 2007). In the hippocampus, dynorphin has been shown to inhibit glutamate release from mossy fiber terminals in the CA3 region and from perforant path afferents to the dentate gyrus and thus block LTP induction (Wagner et al., 1993), and elevation of dynorphin levels in hippocampus may contribute to aging-induced impairment of cognition and spatial learning (Jiang et al., 1989). Hippocampal dynorphin also reduces pilocarpine-induced seizure activity (Bausch and Chavkin, 1997), and elevated dynorphin in hippocampus is believed to be involved in human temporal lobe epilepsy (Houser, 1992). Other effects of dynorphin on brain function have been suggested by the actions of Salvinorin A, a highly selective and potent kappa opioid receptor (KOR) agonist found in salvia divinorum sage (used by natives in South America for thousands of years). Salvinorin A is strongly psychotomimetic and produces hallucinations in humans (Roth et al., 2002). In addition, dynorphin A levels are increased in the cerebrospinal fluid of some types of schizophrenic patients, and opioid antagonists can reverse hallucinations in schizophrenia (Gunne et al., 1977, Heikkilä et al., 1990). These reports suggest an important role for dynorphin/KOR in cognition and perception.
Thus, dynorphin has been found to regulate neuronal excitability broadly in brain and can affect learning, cognition, seizures, nociception, and endocrine function. Recently, activation of the dynorphin/KOR system has also been shown to be necessary and sufficient for stress-induced behavioral responses in animal models of anxiety, depression, and drug seeking behaviors. This review will highlight the recently defined neurobehavioral interactions between CRF and dynorphin, and discuss recent evidence that links these two systems in the modulation of mood state.
Section snippets
Overview of the pharmacology of CRF receptors and kappa opioid receptors
Since the initial discovery of CRF, a large family of CRF-related ligands and receptors have been discovered and pharmacologically characterized. The mammalian CRF family members include CRF, urocortin 1, urocortin 2, and urocortin 3 (Bale and Vale, 2004). These peptide ligands activate two different receptors in a variety of tissues. Both CRF receptors are class B, G-protein coupled receptors (GPCR) and to date, CRF1-R and CRF2-R receptor genes have been identified, with a near 70% amino acid
Kappa opioid system and stress-induced behaviors
Stress-induced opioid peptide release has been reported for all three opioid systems (e.g. β-endorphin, enkephalin and dynorphin), and this release has been demonstrated to be associated with stress-induced analgesic effects in rodent models. Forced swim stress (FSS) in mice has been demonstrated to increase stress-induced analgesic responses in a mu-opioid dependent manner (Rubinstein et al., 1996). In addition, delta-opioid receptor agonists reduce swim-stress-induced immobility in the FSS
Dynorphin/KOR and drug seeking
Building on this prior work and early evidence that implicated a role for the KOR in producing dysphoric responses in humans (Pfeiffer et al., 1986), studies using neurochemical and electrophysiological methods demonstrated that KOR activation in mesolimbic structures including the ventral tegmental area and nucleus accumbens decreased dopamine transmission (Werling et al., 1998, Margolis et al., 2003). Co-administration of KOR agonists with cocaine also inhibited the induction of cocaine
CRF and drug seeking
One of the primary mechanisms for relapse to drug seeking in humans is stress exposure (Kreek et al., 2009). In addition, the neuronal systems involved in stress-regulation undergo changes and alterations in response to the presence of the drug of abuse, which can later affect the persistence of drug taking by the individual (Koob and Le Moal, 2008). For instance, the CRF-regulated hypothalamic–pituitary axis and the central brain stress circuits lose equilibrium following chronic drug
The CRF-dynorphin/KOR connection
Early reports established a potential serial relationship of CRF-induced dynorphin release between the two systems, in vivo (Nikolarakis et al., 1986, Song and Takemori, 1992). Using spinal cord preparations coupled with radioimmunoassay these two reports were the first to show that CRF induces dynorphin release. Recent evidence has demonstrated that dynorphin/KOR signaling occurs downstream of CRF release because the KOR antagonist norBNI blocks CRF-induced conditioned place aversion, and
Dynorphin/KOR and the allostatic model of addiction
One of the leading views in understanding the conceptual framework for how the mammalian brain becomes addicted includes the notion that the brain strives to maintain equilibrium (Koob and Le Moal, 2008). This concept is defined as allostasis, or stability through reorganization (McEwen, 1998). Allostatic processes are believed to be responsible for altering homeostatic processes via changing baseline conditions to such levels that a disease pathology arises. Examples of this include the
Future investigations arising
The mounting evidence demonstrating that stress induces dynorphin release and KOR activation, as a consequence of activation by the CRF system is only the beginning of a long series of investigations required to dissect the mechanisms governing these effects. In the report of Bruchas et al. (2007a) and study of Land et al. (2008a), it was demonstrated that stress and CRF cause KOR activation in several key brain structures associated with reward, stress, and pathologies such as addiction and
Summary
A chief tenant of addiction is the development of negative emotional responses during drug abstinence. The neuropharmacology underlying these processes is only now being evaluated, but is believed to be due to a reduction in reward circuits and an increase in anti-reward systems including dynorphin/KOR. Two major neuropeptide systems that mediate these effects are CRF and dynorphin. Recent work has demonstrated a direct causal connection between stress-induced CRF release initiating dynorphin
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