Modulation of central nervous system actions of corticotropin-releasing factor by dynorphin-related peptides

doi:10.1016/0006-8993(89)90713-0

Brain Research

Volume 488, Issues 1–2, 29 May 1989, Pages 233-240

https://doi.org/10.1016/0006-8993(89)90713-0 Get rights and content

Abstract

Corticotropin-releasing factor (CRF) and dynorphin-related peptides are co-localized within a subset of hypothalamic neurons suggesting the possibility of their co-release. Therefore, studies were performed in conscious unrestrained rats to examine whether dynorphin-related peptides modify the central nervous system (CNS) actions of CRF on sympathetic nervous activity and cardiovascular function. Intracerebroventricular (i.c.v.) administration of dynorphin A_1–18 (0.1 and 1.0 nmol) did not alter arterial pressure (AP) or heart rate (HR). I.c.v. injection of dynorphin A_1–13 (0.1, 0.3 and 1.0 nmol) produced transient elevations of HR but did not significantly affect AP. I.c.v. administration of dynorphin A_1–17 (0.1, 0.3 and 1.0 nmol) elicited delayed (10–15 min) and transient elevations of AP and HR. CRF (0.15 nmol, i.c.v.) produced immediate and sustained elevations of AP, HR and plasma catecholamine levels. Upon simultaneous administration, 0.1 nmol of dynorphin A_1–17, but not 0.1 nmol of dynorphin A_1–8 or dynorphin A_1–13, markedly attenuated CRF-induced elevations of AP, HR, and plasma catecholamine levels. The results suggest that selected dynorphin-related peptides may modify the CNS actions of CRF.

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Furthermore, KOR antagonism/gene deletion has previously been shown to block CRF-induced anxiety-like behavior [35,42]. There is also evidence to suggest directionality of the CRF/DYN interaction in the reverse since KOR activation also stimulates the release of CRF [107,108] and KOR agonist-induced reinstatement of cocaine [33] and alcohol [52] seeking can be blocked with a CRF antagonist. To help elucidate the nature of this relationship, future studies in our lab will investigate whether U50,488-induced reinstatement of nicotine seeking can be blocked with a CRF antagonist and conversely, whether CRF-induced reinstatement of nicotine seeking can be blocked with nor-BNI.
The correlation between stress and smoking is well established. The mechanisms that underlie this relationship are, however, unclear. Recent data suggest that the kappa-opioid system is involved in the mediation of negative affective states associated with stress thereby promoting drug addiction and relapse. Pharmacological treatments targeting the kappa-opioid system and this mechanism may prove to be useful therapeutics for nicotine addiction in the future.
We sought to determine whether there was a stress-specific role of the kappa-opioid system in nicotine seeking behavior.
Groups of male Long Evans rats were trained to self-administer nicotine intravenously; their operant responding for nicotine was extinguished prior to tests of reinstatement. Pretreatment with systemic injections of the kappa-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was given prior to tests of stress (systemic injections of yohimbine (YOH)) or cue-induced reinstatement of nicotine seeking. Systemic injections of the KOR agonist U50,488 were also given in a test for reinstatement of nicotine seeking.
Nor-BNI pretreatment at 1 h and 24 h prior to testing was able to block YOH-induced, but not cue-induced reinstatement of nicotine seeking. U50,488 reinstated nicotine seeking behavior in a dose-dependent manner.
These findings support the hypothesis that the kappa-opioid system is involved in relapse to nicotine seeking induced by stress, but not by conditioned cues. KOR antagonists such as nor-BNI may therefore be useful novel therapeutic agents for decreasing the risk of stress-induced drug relapse.
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KOR agonists stimulate the hypothalamic–pituitary–adrenal (HPA) axis in rodents (Laorden, Fuertes, Gonzalez-Cuello, & Milanes, 2000) and humans (Ur, Wright, Bouloux, & Grossman, 1997), which is primarily regulated by CRF release in the hypothalamus (Vale et al., 1983). DYN has also been found to modulate the effects of CRF on autonomic function (Overton & Fisher, 1989). In the basolateral amygdala, CRF increases KOR immunoreactivity (Bruchas et al., 2009; Land et al., 2008).
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Corticotropin-releasing factor (CRF), a 41 amino acid peptide, was discovered as a key signal in mediating neuroendocrine, autonomic, and behavioral responses to stress. It was revealed later that there exist additional CRF-like peptides, termed urocortins. The CRF receptor subtype 1 (CRF1 receptor) is predominant in the brain whereas subtype 2 (CRF2 receptor) is highly expressed in the brain and the heart. Both centrally and peripherally administered CRF and urocortins produce significant hemodynamic effects via activation of CRF receptors in the brain and the heart. CRF and urocortins are important neural and cardioactive hormones, and are potentially useful therapy for heart failure.
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It was previously reported that systemic administration of the nonselective opioid antagonist, naltrexone, induces Fos-like immunoreactivity (FLI) within the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (lateral–dorsal division; BSTLD), nucleus accumbens shell (NACshell) and ventral tegmental area (VTA) of free-feeding rats. These findings suggest that cellular activity in these brain regions is subject to opioid-mediated inhibitory control under basal conditions. Considering the involvement of mesoaccumbens dopamine neurons and components of the `extended amygdala' in motivated behavior and reward, it was hypothesized that the induction of c-Fos by naltrexone accounts for the motivational-affective consequences of opioid antagonism. In Experiment 1, naltrexone was administered intracerebroventricularly (i.c.v.; 100 μg) to determine whether results obtained in the prior immunohistochemical studies could be attributed to blockade of opioid receptors in brain as opposed to peripheral tissues that convey visceral sensory inputs to the CeA and BSTLD. Naltrexone produced a marked increase in FLI within the CeA and BSTLD, and a moderate increase in NACshell. In Experiment 2, the κ opioid antagonist, nor-binaltorphimine (Nor-BNI; 20.0 μg, i.c.v.) reproduced the effect of naltrexone in BSTLD and CeA, suggesting that the induction of c-Fos in these two structures is a consequence of κ receptor blockade. The selective μ antagonist, CTAP (2.0 μg, i.c.v.), reproduced the effect of naltrexone in NACshell, suggesting that the induction of c-Fos in this structure is a consequence of μ receptor blockade. The functional implications of these results are discussed in terms of the known functions of these brain regions and opioid receptor types, and the prior observation that chronic food restriction eliminates the FLI induced by naltrexone in CeA and BSTLD. It is suggested that tonic μ opioid-mediated inhibition in NACshell has a predisposing effect on goal–approach behavior in general while κ opioid-mediated inhibition in CeA and BSTLD has a predisposing effect on palatability-driven feeding in particular. Finally, a possible relationship between food restriction-induced suppression of the κ opioid mechanism in CeA/BSTLD, local CRH function, and sensitization of the neural substrate for incentive-motivating effects of abused drugs is discussed.

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Modulation of central nervous system actions of corticotropin-releasing factor by dynorphin-related peptides

Abstract

Brain Research

Regul. Pept.

Neuropeptides

Life Sci.

Brain Research

Regul. Pept.

Peptides

Brain Research

Eur. J. Pharmacol.

Brain Research

Life Sci.