Dynorphin/kappa Opioid Receptor Research Articles

Cocaine self-administration augments kappa opioid receptor system-mediated inhibition of dopamine activity in the mesolimbic dopamine system.

Prior studies examining the effects of cocaine on the dynorphin/kappa opioid receptor (Dyn/KOR) system primarily focus on non-contingent cocaine exposure, but the effects of self-administration, which more closely reflects human drug-taking behaviors, are not well studied. In this study we characterized the effects of escalated intravenous cocaine self-administration on the functional state of the Dyn/KOR system and its interaction with mesolimbic dopamine signaling. Rats self-administered cocaine in an extended access, limited intake cocaine procedure, in which animals obtained 40 infusions per day (1.5mg/kg/inf) for 5 consecutive days to ensure comparable consumption levels. Following single day tests of cue reactivity and progressive ratio responding, quantitative real-time polymerase chain reaction was used to measure levels of Oprk and Pdyn transcripts in the ventral tegmental area and nucleus accumbens. Additionally, after self-administration, ex vivo fast-scan cyclic voltammetry in the NAc was used to examine the ability of the KOR agonist U50,488 to inhibit dopamine release. We found that KOR-induced inhibition of dopamine release was enhanced in animals that self-administered cocaine compared to controls, suggesting upregulated Dyn/KOR activity after cocaine self-administration. Furthermore, expression levels of Pdyn in the nucleus accumbens and ventral tegmental area, and Oprk in the nucleus accumbens, were elevated in cocaine animals compared to controls. Additionally, Pdyn expression in the nucleus accumbens was negatively correlated with progressive ratio breakpoints, a measure of motivation to self-administer cocaine. Overall, these data suggest that cocaine self-administration elevates KOR/Dyn system activity in the mesolimbic dopamine pathway.

Comorbidities Are Complex: The Dynorphin/Kappa Opioid Receptor System in a Preclinical Model of Stress and Alcohol

SEE CORRESPONDING ARTICLE ON PAGE 1019 Dynorphin/Kappa Opioid Receptor Activity Within the Extended Amygdala Contributes to Stress-Enhanced Alcohol Drinking in MiceBiological PsychiatryVol. 91Issue 12PreviewWhile there is high comorbidity of stress-related disorders and alcohol use disorder, few effective treatments are available and elucidating underlying neurobiological mechanisms has been hampered by a general lack of reliable animal models. Here, we use a novel mouse model demonstrating robust and reproducible stress-enhanced alcohol drinking to examine the role of dynorphin/kappa opioid receptor (DYN/KOR) activity within the extended amygdala in mediating this stress-alcohol interaction. Full-Text PDF

Kappa-opioid receptor activation reinstates nicotine self-administration in mice

Voluntary drug administration is a key facet of substance use disorder (SUD). Among the substances included under SUD, nicotine is the leading cause of preventable death. Nicotine use is also particularly sensitive to relapse, with stress being the major cause. Intravenous self-administration of nicotine has been the gold standard for accurately modeling SUD in rat and non-human primate models. However, this has been hard to achieve in mice. Here, using previously published protocols, we show that mice develop and maintain intravenous self-administration for nicotine and cocaine. Furthermore, we demonstrate that dynorphin-Kappa opioid receptor signaling, previously established to be necessary for negative affective behavior associated with stress, is sufficient to reinstate nicotine seeking in mice. With a stable model for volitional nicotine-seeking, we will be able to uncover the circuit- and molecular-level adaptations during the development, maintenance, withdrawal and relapse to pathological nicotine use.

Dynorphin/Kappa Opioid Receptor Activity Within the Extended Amygdala Contributes to Stress-Enhanced Alcohol Drinking in Mice

BackgroundWhile there is high comorbidity of stress-related disorders and alcohol use disorder, few effective treatments are available and elucidating underlying neurobiological mechanisms has been hampered by a general lack of reliable animal models. Here, we use a novel mouse model demonstrating robust and reproducible stress-enhanced alcohol drinking to examine the role of dynorphin/kappa opioid receptor (DYN/KOR) activity within the extended amygdala in mediating this stress-alcohol interaction. MethodsMice received repeated weekly cycles of chronic intermittent ethanol exposure alternating with weekly drinking sessions ± forced swim stress exposure. Pdyn messenger RNA expression was measured in the central amygdala (CeA), and DYN-expressing CeA neurons were then targeted for chemogenetic inhibition. Finally, a KOR antagonist was microinjected into the CeA or bed nucleus of the stria terminalis to examine the role of KOR signaling in promoting stress-enhanced drinking. ResultsStress (forced swim stress) selectively increased alcohol drinking in mice with a history of chronic intermittent ethanol exposure, and this was accompanied by elevated Pdyn messenger RNA levels in the CeA. Targeted chemogenetic silencing of DYN-expressing CeA neurons blocked stress-enhanced drinking, and KOR antagonism in the CeA or bed nucleus of the stria terminalis significantly reduced stress-induced elevated alcohol consumption without altering moderate intake in control mice. ConclusionsUsing a novel and robust model of stress-enhanced alcohol drinking, a significant role for DYN/KOR activity within extended amygdala circuitry in mediating this effect was demonstrated, thereby providing further evidence that the DYN/KOR system may be a valuable target in the development of more effective treatments for individuals presenting with comorbidity of stress-related disorders and alcohol use disorder.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Molecular mechanisms of trigeminal neuralgia: A systematic review

ObjectiveTo conduct a systematic review of the available literature for primary research articles identifying potential gene mutations, polymorphisms and other molecular regulatory mechanisms related to trigeminal neuralgia in order to identify the genetic and molecular models of primary trigeminal neuralgia currently being investigated. MethodsPubMed and Web of Science were systematically searched to identify primary research articles discussing genetic predictors of trigeminal neuralgia and neuropathic pain that were published prior to July 2020. This review was conducted according to PRISMA guidelines. ResultsOut of the 333 articles originally identified, a total of 14 papers were selected for study inclusion. These articles included 5 human studies, 6 mouse studies and 3 rat studies. Four articles investigated sodium channels, 1 investigated a sodium channel and nerve growth factor receptor, 2 investigated potassium channels, 1 investigated calcium channels, 1 investigated the downstream regulatory element antagonist modulator protein, 1 investigated the dynorphin-kappa opioid receptor system, 1 investigated TRPA1, 1 investigated the Nrg1/ErbB3/ErbB2 signaling complex, 1 investigated a serotonin transporter and 1 investigated potassium channels, sodium channels, calcium channels, chloride channels, TRP channels and gap junctions. ConclusionResearchers have identified multiple genetic and molecular targets involved with potential pathophysiologies that have a relationship to the creation of trigeminal neuralgia. At this time, there does not seem to be clear causal frontrunner, demonstrating the possibility that genetic predisposition to trigeminal neuralgia may involve multiple genes and/or downstream products, such as ion channels.

Adolescent forced swim stress increases social anxiety-like behaviors and alters kappa opioid receptor function in the basolateral amygdala of male rats

Adolescence is a developmental period marked by robust neural alterations and heightened vulnerability to stress, a factor that is highly associated with increased risk for emotional processing deficits, such as anxiety. Stress-induced upregulation of the dynorphin/kappa opioid receptor (DYN/KOP) system is thought to, in part, underlie the negative affect associated with stress. The basolateral amygdala (BLA) is a key structure involved in anxiety, and neuromodulatory systems, such as the DYN/KOP system, can 1) regulate BLA neural activity in an age-dependent manner in stress-naïve animals and 2) underlie stress-induced anxiety in adults. However, the role of the DYN/KOP system in modulating stress-induced anxiety in adolescents is unknown. To test this, we examined the impact of an acute, 2-day forced swim stress (FSS – 10 min each day) on adolescent (~postnatal day (P) 35) and adult Sprague-Dawley rats (~P70), followed by behavioral, molecular and electrophysiological assessment 24 h following FSS. Adolescent males, but not adult males or females of either age, demonstrated social anxiety-like behavioral alterations indexed via significantly reduced social investigation and preference when tested 24 h following FSS. Conversely, adult males exhibited increased social preference. While there were no FSS-induced changes in expression of genes related to the DYN/KOP system in the BLA, these behavioral alterations were associated with alterations in BLA KOP function. Specifically, while GABA transmission in BLA pyramidal neurons from non-stressed adolescent males responded variably (potentiated, suppressed, or was unchanged) to the KOP agonist, U69593, U69593 significantly inhibited BLA GABA transmission in the majority of neurons from stressed adolescent males, consistent with the observed anxiogenic phenotype in stressed adolescent males. This is the first study to demonstrate stress-induced alterations in BLA KOP function that may contribute to stress-induced social anxiety in adolescent males. Importantly, these findings provide evidence for potential KOP-dependent mechanisms that may contribute to pathophysiological interactions with subsequent stress challenges.

Association of variants of prodynorphin promoter 68-bp repeats in caucasians with opioid dependence diagnosis: Effect on age trajectory of heroin use

The dynorphin/kappa opioid receptor (Dyn/KOR) system is involved in reward processing and dysphoria/anhedonia. Exposure to mu-opioid receptor agonists such as heroin increases expression of the prodynorphin gene (PDYN) in the brain. In this study in a Caucasian cohort, we examined the association of the functional PDYN 68-bp repeat polymorphism with opioid use disorders. In this case-control study, 554 subjects with Caucasian ancestry (142 healthy controls, 153 opioid-exposed, but never opioid dependent, NOD, and 259 with an opioid dependence diagnosis, OD) were examined for association of the PDYN 68-bp repeats with the diagnosis of opioid dependence (DSM-IV criteria), with a dimensional measure of heroin exposure (KMSK scale), and age trajectory parameters of heroin use (age of heroin first use, and age of onset of heaviest use). The PDYN 68-bp repeat genotype (classified as: “short-short” [SS], “long-long” [LL], and “short-long” [SL], based on the number of repeats) was not associated with categorical opioid dependence diagnoses. However, the LL genotype was associated with later age of first heroin use than the SS + SL genotype (19 versus 18 years; p < 0.01). This was also confirmed by a significant positive correlation between the number of repeats and the age of first use of heroin, in volunteers with OD (Spearman r = 0.16; p = 0.01). This suggests that the functional PDYN 68-bp repeat genotype is associated with the age of first use of heroin in Caucasians diagnosed with opioid dependence.

Dynorphin-kappa opioid receptor activity in the central amygdala modulates binge-like alcohol drinking in mice

Although previous research has demonstrated a role for kappa opioid receptor-mediated signaling in escalated alcohol consumption associated with dependence and stress exposure, involvement of the dynorphin/kappa opioid receptor (DYN/KOR) system in binge-like drinking has not been fully explored. Here we used pharmacological and chemogenetic approaches to examine the influence of DYN/KOR signaling on alcohol consumption in the drinking-in-the-dark (DID) model of binge-like drinking. Systemic administration of the KOR agonist U50,488 increased binge-like drinking (Experiment 1) while, conversely, systemic administration of the KOR antagonist nor-BNI reduced drinking in the DID model (Experiment 2). These effects of systemic KOR manipulation were selective for alcohol as neither drug influenced consumption of sucrose in the DID paradigm (Experiment 3). In Experiment 4, administration of the long-acting KOR antagonist nor-BNI into the central nucleus of the amygdala (CeA) decreased alcohol intake. Next, targeted "silencing" of DYN+ neurons in the CeA was accomplished using a chemogenetic strategy. Cre-dependent viral expression in DYN+ neurons was confirmed in CeA of Pdyn-IRES-Cre mice and functionality of an inhibitory (hM4Di) DREADD was validated (Experiment 5). Activating the inhibitory DREADD by CNO injection reduced binge-like alcohol drinking, but CNO injection did not alter alcohol intake in mice that were treated with control virus (Experiment 6). Collectively, these results demonstrate that DYN/KOR signaling in the CeA contributes to excessive alcohol consumption in a binge-drinking model.

Kappa opioid regulation of depressive-like behavior during acute withdrawal and protracted abstinence from ethanol.

The dynorphin/kappa opioid receptor (DYN/KOR) system appears to be a key mediator of the behavioral effects of chronic exposure to alcohol. Although KOR opioid receptor antagonists have been shown to decrease stress-related behaviors in animal models during acute ethanol withdrawal, the role of the DYN/KOR system in regulating long-term behavioral changes following protracted abstinence from ethanol is not well understood. The objective of the current study was to further explore the role of the DYN/KOR system in regulating stress-related behavioral changes associated with acute withdrawal and protracted abstinence from ethanol. More specifically, the present experiments sought to examine the ability of the KOR antagonist norbinaltorphimine (nor-BNI) to reverse depressive-like behavior in the forced swim test in rats exposed to chronic ethanol. In the first experiment, rats were fed an ethanol or control liquid diet for 28–30 days, and then 24 hours after removal of the diet, were exposed to inescapable swim stress. Immediately following this procedure, rats were injected with nor-BNI (20 mg/kg) or saline and then tested 24 hours later in the forced swim test. A second experiment used a similar procedure to examine the effects of nor-BNI on behavioral changes during protracted abstinence in rats tested in the forced swim test 3 weeks after exposure to the ethanol liquid diet procedure. Ethanol-dependent rats showed increased immobility, which is thought to indicate a depressive-like state, when examined during acute withdrawal and protracted abstinence compared to controls, an effect attenuated by nor-BNI. These results suggest that the DYN/KOR system plays role in mediating both short- and long-term behavioral changes associated with depression following chronic alcohol exposure.

Stress alters social behavior and sensitivity to pharmacological activation of kappa opioid receptors in an age-specific manner in Sprague Dawley rats

The dynorphin/kappa opioid receptor (DYN/KOR) system has been identified as a primary target of stress due to behavioral effects, such as dysphoria, aversion, and anxiety-like alterations that result from activation of this system. Numerous adaptations in the DYN/KOR system have also been identified in response to stress. However, whereas most studies examining the function of the DYN/KOR system have been conducted in adult rodents, there is growing evidence suggesting that this system is ontogenetically regulated. Likewise, the outcome of exposure to stress also differs across ontogeny. Based on these developmental similarities, the objective of this study was to systematically test effects of a selective KOR agonist, U-62066, on various aspects of social behavior across ontogeny in non-stressed male and female rats as well as in males and females with a prior history of repeated exposure to restraint (90 min/day, 5 exposures). We found that the social consequences of repeated restraint differed as a function of age: juvenile stress produced substantial increases in play fighting, whereas adolescent and adult stress resulted in decreases in social investigation and social preference. The KOR agonist U-62066 dose-dependently reduced social behaviors in non-stressed adults, producing social avoidance at the highest dose tested, while younger animals displayed reduced sensitivity to this socially suppressing effect of U-62066. Interestingly, in stressed animals, the socially suppressing effects of the KOR agonist were blunted at all ages, with juveniles and adolescents exhibiting increased social preference in response to certain doses of U-62066. Taken together, these findings support the hypothesis that the DYN/KOR system changes with age and differentially responds and adapts to stress across development.

Species differences in the effects of the κ-opioid receptor antagonist zyklophin.

We have shown that dysregulation of the dynorphin/kappa-opioid receptor (DYN/KOR) system contributes to escalated alcohol self-administration in alcohol dependence and that KOR antagonists with extended durations of action selectively reduce escalated alcohol consumption in alcohol-dependent animals. As KOR antagonism has gained widespread attention as a potential therapeutic target to treat alcoholism and multiple neuropsychiatric disorders, we tested the effect of zyklophin (a short-acting KOR antagonist) on escalated alcohol self-administration in rats made alcohol-dependent using intermittent alcohol vapor exposure. Following dependence induction, zyklophin was infused centrally prior to alcohol self-administration sessions and locomotor activity tests during acute withdrawal. Zyklophin did not impact alcohol self-administration or locomotor activity in either exposure condition. To investigate the neurobiological basis of this atypical effect for a KOR antagonist, we utilized a κ-, μ-, and δ-opioid receptor agonist-stimulated GTPyS coupling assay to examine the opioid receptor specificity of zyklophin in the rat brain and mouse brain. In rats, zyklophin did not affect U50488-, DAMGO-, or DADLE-stimulated GTPyS coupling, whereas the prototypical KOR antagonist nor-binaltorphimine (norBNI) attenuated U50488-induced stimulation in the rat brain tissue at concentrations that did not impact μ- and δ-receptor function. To reconcile the discrepancy between the present rat data and published mouse data, comparable GTPyS assays were conducted using mouse brain tissue; zyklophin effects were consistent with KOR antagonism in mice. Moreover, at higher concentrations, zyklophin exhibited agonist properties in rat and mouse brains. These results identify species differences in zyklophin efficacy that, given the rising interest in the development of short-duration KOR antagonists, should provide valuable information for therapeutic development efforts.

Erratum: J Reprod Dev, Vol. 59, No. 3, p. 266-272, Dynorphin-Kappa Opioid Receptor Signaling Partly Mediates Estrogen Negative Feedback Effect on LH Pulses in Female Rats.

Figure 3(a) have been corrected.

Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward

The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and was positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease.

Protracted withdrawal from ethanol and enhanced responsiveness stress: Regulation via the dynorphin/kappa opioid receptor system

Although recent work suggests that the dynorphin/kappa opioid receptor (DYN/KOR) system may be a key mediator in the stress-related effects of alcohol, the regulation of long-term changes associated with protracted withdrawal from ethanol via the DYN/KOR system has yet to be explored. The objective of the present study was to determine the role of the DYN/KOR system in the regulation of anxiety-related behaviors during an extended period of abstinence from ethanol in animals with a history of ethanol dependence. Male Wistar rats (n = 94) were fed an ethanol or control liquid diet for 25–30 days. Six weeks after its removal, rats were exposed to 20 min of immobilization, and the ability of the KOR antagonist nor-binaltorphimine (nor-BNI) (0–20 mg/kg, intraperitoneal [i.p.]) to attenuate the enhanced responsiveness to stress observed in rats chronically exposed to ethanol was investigated using the elevated plus maze. In addition, the ability of U50,488 (0–10 mg/kg, i.p.) to prime anxiety-like behavior during protracted withdrawal was also examined. Rats with a history of ethanol dependence showed a significant decrease in open-arm exploration after exposure to restraint, indicating an anxiety-like state, compared to similarly treated controls, an effect that was blocked by nor-BNI. nor-BNI also selectively decreased center time and open-arm approaches in ethanol-exposed rats. The highest dose of U50,488 decreased open-arm exploration and the total number of arm entries in ethanol-exposed and control rats. Although lower doses of U50,488 did not affect open-arm exploration in either group, the 0.1 mg/kg dose selectively decreased motor activity in the ethanol-exposed rats when compared to similarly pretreated controls. These findings further support the hypothesis that behaviors associated with withdrawal from ethanol are in part regulated by the DYN/KOR system, and suggest that these effects may be long lasting in nature.

Dynorphin-Kappa Opioid Receptor Signaling Partly Mediates Estrogen Negative Feedback Effect on LH Pulses in Female Rats

Accumulating evidence suggests that the arcuate nucleus (ARC) kisspeptin/neurokinin B (NKB)/dynorphin (KNDy) neurons play a role in estrogen negative feedback action on pulsatile gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) release. The present study aimed to determine if dynorphin (Dyn) is involved in estrogen negative feedback on pulsatile GnRH/LH release. The effect of the injection of nor-binaltorphimine (nor-BNI), a kappa-opioid receptor (KOR) antagonist, into the third cerebroventricle (3V) on LH pulses was determined in ovariectomized (OVX) adult female rats with/without replacement of negative feedback levels of estradiol (low E2). The mean LH concentrations and baseline levels of LH secretion in nor-BNI-injected, low E2-treated rats were significantly higher compared with vehicle-treated controls. On the other hand, the nor-BNI treatment failed to affect any LH pulse parameters in OVX rats without low E2 treatment. These results suggest that Dyn is involved in the estrogen negative feedback regulation of pulsatile GnRH/LH release. The low E2 treatment had no significant effect on the numbers of ARC Pdyn (Dyn gene)-,Kiss1- and Tac2 (NKB gene)-expressing cells. The treatment also did not affect mRNA levels of Pdyn and Oprk1 (KOR gene) in the ARC-median eminence region, but significantly increased the ARC kisspeptin immunoreactivity. These findings suggest that the negative feedback level of estrogen suppresses kisspeptin release from the ARC KNDy neurons through an unknown mechanism without affecting the Dyn and KOR expressions in the ARC. Taken together, the present result suggests that Dyn-KOR signaling is a part of estrogen negative feedback action on GnRH/LH pulses by reducing the kisspeptin release in female rats.

Alcohol-induced plasticity in the dynorphin/kappa-opioid receptor system

Alcoholism is a chronic relapsing disorder characterized by continued alcohol use despite numerous adverse consequences. Alcohol has been shown to interact with numerous neurotransmitter systems to exert its pharmacological effects. The endogenous opioid system (EOS) has been strongly implicated in the positive and negative reinforcing effects of alcohol. Traditionally recognized as dysphoric/anhedonic in nature, the dynorphin/kappa-opioid receptor (DYN/KOR) system has recently received considerable attention due to evidence suggesting that an upregulated DYN/KOR system may be a critical contributor to the complex factors that result in escalated alcohol consumption once dependent. The present review will discuss alcohol-induced plasticity in the DYN/KOR system and how these neuroadaptations could contribute to excessive alcohol seeking and consumption.

The role of endogenous dynorphin in ethanol-induced state-dependent CPP

The aim of this study was to determine the role of the endogenous dynorphin/kappa opioid receptor (DYN/KOP) system in ethanol-induced state-dependent conditioned place preference (CPP). To this end, mice lacking the pro-DYN gene and their wild-type littermates/controls were tested for baseline place preference on day 1, received 15-min morning and afternoon conditionings with saline or ethanol (2 g/kg) each day for three consecutive days and were then tested for CPP under a drug-free state on day 5 and following a saline or ethanol (1 or 2 g/kg) challenge on day 8. Given that compensatory developmental changes may occur in knockout mice, the effect of nor-binaltorphimine (nor-BNI), a KOP antagonist, on state-dependent CPP induced by ethanol was also studied in wild-type mice. On day 1, mice were tested for baseline place preference and, 4 h later, treated with saline or nor-BNI (10 mg/kg). On days 2–4, mice received 15-min morning and afternoon conditionings and were tested for CPP under a drug-free state on day 5 and following an ethanol (1 g/kg) challenge on day 8. A comparable CPP was observed in mice lacking the pro-DYN gene and their wild-type littermates/controls as well as in wild-type mice treated with nor-BNI and their saline-treated controls. However, these mice compared to their respective controls exhibited a greater CPP response following an ethanol (1 g/kg) challenge, suggesting that the endogenous DYN/KOP system may negatively regulate ethanol-induced state-dependent CPP.

Trigeminal injury causes kappa opioid-dependent allodynic, glial and immune cell responses in mice.

BackgroundThe dynorphin-kappa opioid receptor (KOR) system regulates glial proliferation after sciatic nerve injury. Here, we investigated its role in cell proliferation following partial ligation of infraorbital nerve (pIONL), a model for trigeminal neuropathic pain. Mechanical allodynia was enhanced in KOR gene deleted mice (KOR-/-) compared to wild type mice. Using bromodeoxyuridine (BrdU) as a mitotic marker, we assessed cell proliferation in three different areas of the trigeminal afferent pathway: trigeminal nucleus principalis (Vp), trigeminal root entry zone (TREZ), and trigeminal ganglion (TG).ResultsIn KOR-/- mice or norBNI-treated mice, the number of proliferating cells in the Vp was significantly less than in WT mice, whereas cell proliferation was enhanced in TREZ and TG. The majority of the proliferating cells were nestin positive stem cells or CD11b positive microglia in the Vp and macrophages in the TG. GFAP-positive astrocytes made a clear borderline between the CNS and the PNS in TREZ, and phosphorylated KOR staining (KOR-p) was detectable only in the astrocytes in CNS in WT mice but not in KOR-/- or norBNI-treated mice.ConclusionsThese results show that kappa opioid receptor system has different effects after pIONL in CNS and PNS: KOR activation promotes CNS astrocytosis and microglial or stem cell proliferation but inhibits macrophage proliferation in PNS. The trigeminal central root has a key role in the etiology and treatment of trigeminal neuralgia, and these newly identified responses may provide new targets for developing pain therapies.

Repeated swim stress induces kappa opioid-mediated activation of extracellular signal-regulated kinase 1/2.

Earlier studies identified the dynorphin-kappa opioid receptor (KOR) system as a critical mediator of dysphoria-induced aversion after repeated stress exposure, but the molecular signaling mechanisms were not fully characterized. In this study we report that repeated forced swim stress caused a significant phosphorylation of extracellular signal-regulated kinase (ERK)1/2 a mitogen-activated protein kinase (MAPK) in both the caudate and nucleus accumbens regions of the mouse striatum. Activation was blocked by the KOR antagonist, norbinaltorphimine, and absent in KOR knockout mice. In contrast to p38-MAPK activation by stress-induced dynorphin release, KOR-mediated ERK1/2 phosphorylation was not dependent on G-protein coupled receptor kinase 3 expression. These results indicate stress-induced activation of the dynorphin-KOR systems activates ERK1/2 MAPK signaling, and this may contribute to the behavioral responses to repeated stress exposure.