Endogenous Kappa-opioid Systems Research Articles

Kappa Opioid Receptor Ligands and Pharmacology: Diphenethylamines, a Class of Structurally Distinct, Selective Kappa Opioid Ligands.

The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system. The endogenous kappa opioid system is expressed in the central and peripheral nervous systems, and has a key role in modulating pain in central and peripheral neuronal circuits and a wide array of physiological functions and neuropsychiatric behaviors (e.g., stress, reward, emotion, motivation, cognition, epileptic seizures, itch, and diuresis). We review the latest advances in pharmacology of the KOR, chemical developments on KOR ligands with advances and challenges, and therapeutic and potential applications of KOR ligands. Diverse discovery strategies of KOR ligands targeting natural, naturally derived, and synthetic compounds with different scaffolds, as small molecules or peptides, with short or long-acting pharmacokinetics, and central or peripheral site of action, are discussed. These research efforts led to ligands with distinct pharmacological properties, as agonists, partial agonists, biased agonists, and antagonists. Differential modulation of KOR signaling represents a promising strategy for developing pharmacotherapies for several human diseases, either by activating (treatment of pain, pruritus, and epilepsy) or blocking (treatment of depression, anxiety, and addiction) the receptor. We focus on the recent chemical and pharmacological advances on diphenethylamines, a new class of structurally distinct, selective KOR ligands. Design strategies and investigations to define structure-activity relationships together with in vivo pharmacology of diphenethylamines as agonists, biased agonists, and antagonists and their potential use as therapeutics are discussed.

Age as a factor in stress and alcohol interactions: A critical role for the kappa opioid system.

The endogenous kappa opioid system has primarily been shown to be involved with a state of dysphoria and aversion. Stress and exposure to drugs of abuse, particularly alcohol, can produce similar states of unease and anxiety, implicating the kappa opioid system as a target of stress and alcohol. Numerous behavioral studies have demonstrated reduced sensitivity to manipulations of the kappa opioid system in early life relative to adulthood, and recent reports have shown that the kappa opioid system is functionally different across ontogeny. Given the global rise in early-life stress and alcohol consumption, understanding how the kappa opioid system responds and adapts to stress and/or alcohol exposure differently in early life and adulthood is imperative. Therefore, the objective of this review is to highlight and discuss studies examining the impact of early-life stress and/or alcohol on the kappa opioid system, with focus on the documented neuroadaptations that may contribute to future vulnerability to stress and/or increase the risk of relapse. We first provide a brief summary of the importance of studying the effects of stress and alcohol during early life (prenatal, neonatal/juvenile, and adolescence). We then discuss the literature on the effects of stress or alcohol during early life and adulthood on the kappa opioid system. Finally, we discuss the few studies that have shown interactions between stress and alcohol on the kappa opioid system and provide some discussion about the need for studies investigating the development of the kappa opioid system.

Sustained pain-related depression of behavior: effects of intraplantar formalin and complete freund's adjuvant on intracranial self-stimulation (ICSS) and endogenous kappa opioid biomarkers in rats.

BackgroundIntraplantar administration of complete Freund's adjuvant (CFA) and formalin are two noxious stimuli commonly used to produce sustained pain-related behaviors in rodents for research on neurobiology and treatment of pain. One clinically relevant manifestation of pain is depression of behavior and mood. This study compared effects of intraplantar CFA and formalin on depression of positively reinforced operant behavior in an assay of intracranial self-stimulation (ICSS) in rats. Effects of CFA and formalin on other physiological and behavioral measures, and opioid effects on formalin-induced depression of ICSS, were also examined.ResultsThere were four main findings. First, consistent with previous studies, both CFA and formalin produced similar paw swelling and mechanical hypersensitivity. Second, CFA produced weak and transient depression of ICSS, whereas formalin produced a more robust and sustained depression of ICSS that lasted at least 14 days. Third, formalin-induced depression of ICSS was reversed by morphine doses that did not significantly alter ICSS in saline-treated rats, suggesting that formalin effects on ICSS can be interpreted as an example of pain-related and analgesic-reversible depression of behavior. Finally, formalin-induced depression of ICSS was not associated with changes in central biomarkers for activation of endogenous kappa opioid systems, which have been implicated in depressive-like states in rodents, nor was it blocked by the kappa antagonist norbinaltorphimine.ConclusionsThese results suggest differential efficacy of sustained pain stimuli to depress brain reward function in rats as assessed with ICSS. Formalin-induced depression of ICSS does not appear to engage brain kappa opioid systems.Electronic supplementary materialThe online version of this article (doi:10.1186/1744-8069-10-62) contains supplementary material, which is available to authorized users.

Pain‐related depression of the mesolimbic dopamine system in rats

Some stressors produce prodepressant behavioral effects by activating endogenous kappa opioid systems that in turn depress mesolimbic dopamine release. This study evaluated the role of this mechanism in pain‐related behavioral depression in rats. Adult male Sprague‐Dawley rats were prepared either with intracranial electrodes targeting the medial forebrain bundle (for behavior studies of intracranial self‐stimulation; ICSS) or cannulae for microdialysis measures of nucleus accumbens dopamine (NAcc DA). Changes in ICSS and NAcc DA were examined after treatment with a chemical noxious stimulus (intraperitoneal injection of dilute acid) or an exogenous kappa agonist (U69593). Additional studies examined sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the mu opioid receptor agonist morphine) or by the kappa antagonist norbinaltorphimine (norBNI). Both acid and U69593 depressed ICSS and NAcc DA release. However, the pain‐related effects of acid were blocked by pretreatment with ketoprofen and morphine, but not by norBNI. Conversely, effects of U69593 were blocked by norBNI but not by ketoprofen, and were only attenuated by morphine. These results support a role for the mesolimbic dopamine system, but not endogenous kappa opioid systems, in mediating pain‐related depression of behavior in rats.

Social Defeat Stress-Induced Behavioral Responses are Mediated by the Endogenous Kappa Opioid System

Previous studies have demonstrated that repeated forced-swim stress-induced behaviors (including analgesia, immobility, and increased drug reward) were mediated by the release of endogenous prodynorphin-derived opioid peptides and subsequent activation of the kappa opioid receptor (KOR). We tested the generality of these effects using a different type of stressful situation: repeated social defeat. C57Bl/6 mice subjected to social defeat stress (SDS) over 3 days showed a characteristic stress-induced immobility and defeated-postural response, as well as stress-induced analgesia (SIA). Daily pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI, 10 mg/kg, i.p.) blocked the SIA and significantly reduced the stress-induced immobility on the second and third days of SDS exposure. In contrast, prodynorphin gene-disrupted mice showed no significant increase in immobility, socially defeated postures, or SIA following repeated exposure to SDS. Since both stress and the kappa opioid system can modulate the response to drugs of abuse, we tested the effects of SDS on cocaine-conditioned place preference (CPP). SDS-exposed mice conditioned with cocaine (15 mg/kg, s.c.) showed significant potentiation of place-preference for the drug-paired chamber over the responses of unstressed mice. Nor-BNI pretreatment blocked stress-induced potentiation of cocaine-CPP. Consistent with this result, mice lacking the prodynorphin gene did not show stress-induced potentiation of cocaine-CPP, whereas wild-type littermates did. The findings suggest that chronic SDS may activate the kappa opioid system to produce analgesia, immobility, social defeat postures, and resulting in a potentiation of the acute rewarding properties of cocaine.

Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance.

Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [kappa opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4-L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the kappa agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.

Animal models of chronic pain: Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance

Animal models of chronic pain: Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance

Modification of morphine dependence under chronic pain and its mechanism

Clinical studies have demonstrated that when opiates are used to control cancer pain, psychological dependence and analgesic tolerance are not a major concern. The present study was, therefore, designed to investigate the modulation of rewarding effects of opiates under inflammatory chronic pain in SD rats. Formalin (2.5%, 50 microliters) or carrageenan (1%, 100 microliters) was injected into the plantar surface of the rat paw. Formalin and carrageenan reduced the paw pressure threshold. The hyperalgesia lasted for 9 to 13 days. Rewarding effect of morphine was evaluated by conditioned place preference paradigm. Morphine produced a significant place preference. This effect was significantly attenuated in inflamed groups as compared with the respective non-inflamed groups. Furthermore, the morphine-induced place preference in the inflamed group gradually recovered to the respective control level as the inflammation healed. On the other hand, we found that kappa-opioid receptor agonists markedly inhibit rewarding effect of mu-opioid receptor agonists. Therefore, to elucidate the mechanism of this attenuation, the effects of pretreatment with kappa- and delta-opioid receptor antagonists, nor-binaltorphimine (nor-BNI) and naltrindole (NTI), on the development of the morphine-induced place preference under inflammation were examined. Nor-BNI, but not NTI, eliminated the suppression of the morphine-induced place preference in inflamed groups. The morphine-induced increase in dopamine turnover in the limbic forebrain was suppressed under inflammation, and the suppression was abolished by the pretreatment with nor-BNI. These results suggest that endogenous kappa-opioid systems may be activated by chronic inflammatory nociception, resulting in the suppression of the development of rewarding effects produced by morphine.

Kappa opioid inhibition of morphine and cocaine self-administration in rats

Two kappa agonists, U50,488 and spiradoline, produced dose-related acute decreases in both morphine and cocaine self-administration in rats; higher doses of both agents were required to decrease rates of bar-pressing for water. On the day after kappa agonist administration, both agents produced extinction-like patterns of responding in many rats self-administering morphine or cocaine but not in rats responding for water. Two days after their administration, both U50,488 and spiradoline produced significant decreases in both morphine and cocaine intake; some rats continued to show decreases in drug self-administration for 5–6 days. Although the kappa antagonist nor-binaltorphimine (10 mg/kg s.c.) had no effect itself on either morphine or coccaine self-administration, it fully antagonized the effects of U50,488 (10 m/kg i.p.). The results suggest that although endogenous kappa opioid systems may not tonically modulate mechanisms involved in drug reinforcement, pharmacological activation of kappa pathways may be a novel and effective pharmacological approach to treating both opioid and stimulant addiction.

The effects of the kappa agonist PD-117302 on feeding behaviour in obese and lean Zucker rats

It has been suggested that supersensitivity to, or overactivity of, endogenous opioid systems, particularly the dynorphin system, may be important in the development of obesity in the obese mouse (ob/ob). We have investigated the possibility that an increase in sensitivity to kappa agonists may also play a role in the development of obesity in another mutant rodent, the Zucker rat. The effects of the selective kappa agonist PD-117302 were investigated in both lean and obese Zucker rats. The lean animals appeared to be more sensitive to the initial hyperphagic effects of PD-117302 than their obese littermates, although this initial hyperphagia was followed by a subsequent decrease in food intake so that by the end of the six-hour test period the animals treated with PD-117302 had eaten less than the saline-treated controls. These changes in food intake were parallelled by increases and decreases in the duration of time spent feeding throughout the experiment. At the doses used in this study PD-117302 had no effect on locomotor activity. It is concluded that obese Zucker rats are not more sensitive to the hyperphagic effects of the kappa agonist PD-117302 than their lean littermates and therefore it seems unlike that increased sensitivity to an endogenous kappa opioid system plays a major part in the overeating and obesity observed in this strain of rat.