Kappa-opioid Receptor Stimulation Research Articles

Stimulation of kappa opioid receptors in the nucleus accumbens promotes feeding behavior in mice: Acute restoration of feeding during anorexia induced by 5-fluorouracil

Though μ and δ opioid receptors are reported to regulate energy homeostasis, any role for κ opioid receptors in these processes remains unclear. The present study investigated the role of κ opioid receptors in regulation of feeding behavior and plasma glucose levels using nalfurafine, a κ opioid receptor agonist used clinically. Systemic injection of nalfurafine increased food intake under non-fasted conditions, but not after food deprivation, and this effect was inhibited by the κ opioid receptor antagonist norbinaltorphimine. In contrast, nalfurafine did not affect plasma glucose levels. I.c.v. injection of nalfurafine increased food intake, whereas systemic injection of nalfurafine methiodide, which does not penetrate the blood brain barrier, was without effect. In addition, nalfurafine tended to increase preproorexin mRNA in the hypothalamus. However, neither the orexin OX1 receptor antagonist YNT-1310 nor the non-selective orexin receptor antagonist suvorexant inhibited the increase in food intake induced by nalfurafine. While nalfurafine injected into the lateral hypothalamus did not affect food intake, nalfurafine injected into the nucleus accumbens increased food intake, which was inhibited by norbinaltorphimine. Finally, we examined the effect of nalfurafine on anorexia induced by the anti-cancer agent 5-fluorouracil. Reduced food intake at 2 days following 5-fluorouracil administration was alleviated across the first 3 h following daily injection of nalfurafine, though daily food intake was not influenced. These results indicate that nalfurafine promotes feeding behavior through stimulation of κ opioid receptors in the nucleus accumbens and may be a candidate for reducing anorexia due to anti-cancer agents.

Kappa-opioid receptor stimulation in the nucleus accumbens shell and ethanol drinking: Differential effects by rostro-caudal location and level of drinking

Although the kappa-opioid receptor (KOR) and its endogenous ligand, dynorphin, are believed to be involved in ethanol drinking, evidence on the direction of their effects has been mixed. The nucleus accumbens (NAc) shell densely expresses KORs, but previous studies have not found KOR activation to influence ethanol drinking. Using microinjections into the NAc shell of male and female Long-Evans rats that drank under the intermittent-access procedure, we found that the KOR agonist, U50,488, had no effect on ethanol drinking when injected into the middle NAc shell, but that it promoted intake in males and high-drinking females in the caudal NAc shell and high-drinking females in the rostral shell, and decreased intake in males and low-drinking females in the rostral shell. Conversely, injection of the KOR antagonist, nor-binaltorphimine, stimulated ethanol drinking in low-drinking females when injected into the rostral NAc shell and decreased drinking in high-drinking females when injected into the caudal NAc shell. These effects of KOR activity were substance-specific, as U50,488 did not affect sucrose intake. Using quantitative real-time PCR, we found that baseline gene expression of the KOR was higher in the rostral compared to caudal NAc shell, but that this was upregulated in the rostral shell with a history of ethanol drinking. Our findings have important clinical implications, demonstrating that KOR stimulation in the NAc shell can affect ethanol drinking, but that this depends on NAc subregion, subject sex, and ethanol intake level, and suggesting that this may be due to differences in KOR expression.

Sex Differences in Brain Region-Specific Activation of c-Fos following Kappa Opioid Receptor Stimulation or Acute Stress in Mice.

Kappa opioid receptors (KOPr) are involved in the response to stress. KOPr are also targets for the treatment of stress-related psychiatric disorders including depression, anxiety, and addiction although effects of KOPr are often sex-dependent. Here we investigated c-Fos expression in a range of brain regions in male and female mice following an acute stressor, and a single injection of KOPr agonist. Using adult C57BL/6 c-Fos-GFP transgenic mice and quantitative fluorescence microscopy, we identified brain regions activated in response to a challenge with the KOPr agonist U50,488 (20 mg/kg) or an acute stress (15 min forced swim stress, FSS). In male mice, U50,488 increased expression of c-Fos in the prelimbic area of the prefrontal cortex (PFCx), nucleus accumbens (NAcc), and basolateral nuclei of the amygdala (BLA). In contrast, in female mice U50,488 only activated the BLA but not the PFCx or the NAcc. FSS increased activation of PFCx, NAcc, and BLA in males while there was no activation of the PFCx in female mice. In both sexes, the KOPr antagonist norBNI significantly blocked U50,488-induced, but not stress-induced activation of brain regions. In separate experiments, activated cells were confirmed as non-GABAergic neurons in the PFCx and NAcc. Together these data demonstrate sex differences in activation of brain regions that are key components of the 'reward' circuitry. These differential responses may contribute to sex differences in stress-related psychiatric disorders and in the treatment of depression, anxiety, and addiction.

Abstract P242: The Role Of Kappa Opioid Receptors In The Development Of Hypertension And Kidney Injury In Sprague-Dawley Rats

The extensive use of opioid-based pain management strongly correlates with poor cardiovascular and cardiorenal outcomes. Our recent studies suggest that treatment with kappa opioid receptor (KOR) agonist BRL 52537 leads to the progression of chronic kidney disease (CKD) and aggravation of salt-sensitive hypertension. We hypothesize that stimulation of KORs leads to blood pressure elevation, albuminuria, and kidney damage in healthy Sprague-Dawley (SD) rats. To characterize the effect of the KOR agonist BRL 52537 on the development of blood pressure and kidney function in vivo , SD rats were treated with a daily i.v. bolus infusion of BRL 52537 or a corresponding vehicle. To test the contribution of KOR stimulation on calcium homeostasis in podocytes, BRL 52537 was used on freshly isolated glomeruli from SD rats. Single-channel analysis was applied to assess the effect of KORs stimulation on TRPC6 channel activity in the human immortalized podocytes. Chronic treatment with BRL 52537 leads to increased mean arterial pressure (88±1 vs 101±4 mmHg, vehicle vs treated, p<0.05), podocyte basal calcium (90±12 vs 216±16 a.u., vehicle vs treated, p<0.05), and GFB impairment in SD rats which is reflected by a transient increase in albumin excretion (Alb/cre ratio 0.35±0.1 vs 0.72±0.2, vehicle vs treated, p<0.05). Cumulative probability distribution analysis of the glomerular injury score revealed a rightward shift toward a high glomerular injury score in the group treated with BRL 52537 (p<0.05). Angiotensin II level was higher in a BRL-treated group (156±17 vs 232±59 pmol, vehicle vs treated, p=0.065); however, it did not reach a statistical difference. Acute application of BRL 52537 resulted in sustained calcium response (0.23±0.01 a.u., Fluo4/FuraRed, maximum calcium response) in freshly isolated glomeruli from SD rats. Furthermore, patch-clamp experiments in human immortalized podocytes (cell-attached configuration) revealed that BRL 52537 activated TRPC6 channels. Taken together, these data support the hypothesis that administration of opioids in SD rats leads to activation of the KOR/TRPC6 pathway, which in turn led to glomerular filtration barrier impairment, increased glomerular damage, and blood pressure elevation.

Kappa opioid receptor modulation of endometriosis pain in mice

The kappa opioid receptor is a constituent of the endogenous opioid analgesia system widely expressed in somatosensory nervous pathways and also in endometrial tissues. This work investigates the possible involvement of kappa opioid receptor on the nociceptive, behavioral and histopathological manifestations of endometriosis in a murine model. Female mice receiving endometrial implants develop a persistent mechanical hypersensitivity in the pelvic area that is stronger during the estrus phase of the estrous cycle. The kappa opioid receptor agonist U50,488H produces a dose-dependent relief of this mechanical hypersensitivity, regardless of the cycle phase. Repeated exposure to a low dose of U50,488H (1 mg/kg/day s.c. for one month) provides sustained relief of mechanical hypersensitivity, without tolerance development or sedative side effects. Interestingly, this treatment also inhibits a decreased rearing behavior associated with spontaneous pain or discomfort in endometriosis mice. This KOR-mediated pain relief does not prevent the anxiety-like behavior or the cognitive impairment exhibited by endometriosis mice, and the growth of endometriotic cysts is also unaltered. These data provide evidence of strong pain-relieving properties of kappa opioid receptor stimulation in female mice with endometriosis pain. The persistence of affective and cognitive manifestations suggests that these comorbidities are independent of pelvic pain and simultaneous treatment of these comorbidities may be necessary for successful management of endometriosis.

Input‐specific regulation of discrete populations of Lateral Habenula neurons by Kappa opioid receptors

The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of reward circuitry. Increased activity of the LHb is associated with drug addiction and stress-related mood disorders. Dynorphin (DYN)/Kappa opioid receptor (KOR) signaling is an endogenous mediator of stress response in reward circuitry. Previously, we have shown a novel functional role of DYN/KOR signaling within LHb and its dysregulation by a severe early life stress (maternal deprivation, MD). Specifically, KOR stimulation has distinct effects on LHb neuronal excitability in distinct neuronal populations identified by the presence of hyperpolarizing current (Ih) that were absent following MD. Namely, KOR stimulation through the KOR agonist, U50,488, significantly decreases excitability of Ih negative (Ih-) LHb neurons while simultaneously increasing excitability of Ih positive (Ih+) LHb neurons. Additionally, KOR-induced alteration in LHb excitability is dependent on both presynaptic glutamatergic and GABAergic signaling likely through presynaptic KORs on inputs to LHb neurons. Given that LHb inputs from the entopeduncular nucleus (EP) and lateral hypothalamus (LH) have been implicated in stress-induced mood disorders through modulation of LHb excitability, we hypothesize that the presynaptic effects of KOR stimulation on LHb neuronal activity may be driven by one or both of these inputs. Using selective in vitro optical stimulation of either EP or LH inputs to LHb neurons in brain slices from rats, our pilot study suggests that KOR activation of EP and LH inputs may differentially affect optically evoked action potential generation across Ih- and Ih+ LHb subpopulations. Moreover, our data from MD rats suggest that there may be an imbalance of excitation to inhibition at EP synapses onto LHb neurons. Given that MD increases immunolabeled DYN (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreasing mRNA levels of KORs in LHb, we also investigated MD-induced modulation of a KOR-specific downstream signaling (p38 MAPK). Our molecular data indicate that decreased KOR expression may be a homeostatic response to higher basal activation of KORs by MD-induced increases in DYN and p38 expression in the LHb. Ih- and Ih+ neurons molecular identification is further investigated following electrophysiological recordings by combining ionophoresis labeling during electrophysiology experiments and post-hoc immunohistochemistry to verify the glutamatergic (VGLUT+) and GABAergic (somatostatin, SST+ or parvalbumin, PV) nature of LHb neurons. Collectively, our current studies provide evidence for input- and cell-specific regulation of LHb neurons by KOR signaling that could be modulated by MD and highlights a future hotspot for pharmacological intervention of KOR-mediated mood disorders through dysregulation of specific LHb neural circuits.

Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula

The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb spontaneous neuronal activity and intrinsic excitability while blunting the response of LHb neurons to extrahypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn/KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerted differential effects on the excitability of two distinct sub-populations of LHb neurons that differed in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increased neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreasing neuronal excitability in small/negative Ih (Ih-) neurons. We found that an intact fast-synaptic transmission was required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. While AMPAR-, GABAAR-, or NMDAR-mediated synaptic transmission alone was sufficient to mediate the effects of U50,488 on excitability of Ih- neurons, either GABAAR- or NMDAR-mediated synaptic transmission could mediate these effects in Ih+ neurons. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission where stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons while primarily decreased or in some cases increased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreasing mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. Moreover, the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.

Design, Synthesis, and Characterization of the Macrocyclic Tetrapeptide cyclo[Pro-Sar-Phe-d-Phe]: A Mixed Opioid Receptor Agonist-Antagonist Following Oral Administration.

Substance abuse remains a serious public health crisis, affecting millions of people worldwide. Macrocyclic tetrapeptides like CJ-15,208 and [d-Trp]CJ-15,208 demonstrate opioid activity shown to attenuate the rewarding effects of cocaine in conditioned place preference assays in mice, making them promising lead compounds for treating substance abuse. In the present study, we report the rational design, synthesis, conformational analysis, and continued pharmacological evaluation of the novel macrocyclic tetrapeptide cyclo[Pro-Sar-Phe-d-Phe] to further explore this unique molecular scaffold. This peptide was rationally designed based on X-ray and NMR structures of related macrocyclic tetrapeptides. Following synthesis, its solution-phase conformations were determined by NMR and molecular modeling. The peptide adopted multiple conformations in polar solvents, but a single conformation in chloroform that is stabilized by intramolecular hydrogen bonding. The peptide is orally bioavailable, producing antinociception and antagonism of kappa opioid receptor (KOR) stimulation following oral administration in a mouse 55 °C warm-water tail-withdrawal assay. Notably, cyclo[Pro-Sar-Phe-d-Phe] blocked both stress- and drug-induced reinstatement of cocaine and morphine conditioned place preference in mice following oral administration, and displayed a decreased side-effect profile compared to morphine. Thus, cyclo[Pro-Sar-Phe-d-Phe] is a promising lead compound for the treatment of substance abuse.

Humoral immunity and autism spectrum disorders

Abnormal immune activation, particularly of a humoral nature, has consistently been described in the etiopathogenesis of autism spectrum disorders (ASD). In this journal, Mead and Ashwood (2015) reviewed immune abnormalities in autism and linked them to severity of classic autistic symptoms. However, there remains a lack of clarity as to how environmental risk factors in ASD may contribute to such immunophenotypes. The evidence presented herein highlights these immune deficits of a humoral nature in ASD. Moreover, aligned with prior research showing a link between chronic air pollution and suppression of humoral immunity, the author of this commentary has proposed that environmental exposure to pervasive air pollutants, particularly nitrous oxide (N2O), may target several anti-inflammatory biomarkers, including alpha 7 nicotinic acetylcholine receptor (α7nAChR) inhibition and stimulation of kappa opioid receptor (KOR) activity. Given that these physiological targets, in particular, may promote the oft-noted humoral immunophenotypes in ASD, including B cell survival and muted antibody responses, this correspondence supports an existing line of evidence that air pollution, and particularly exposure to environmental N2O, may be an important etiological risk factor in ASD.

Chronic Kappa opioid receptor activation modulates NR2B: Implication in treatment resistant depression.

Psychotomimetic and prodepressive effect by kappa opioid receptor (KOR) activation in rodents and human is widely known. Significantly, recent clinical investigations demonstrated the salutary effects of KOR antagonists in patients with treatment resistant depression, indicating essential role of KOR signaling in refractory depression. This study was undertaken to reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine or citalopram. Further, chronic KOR activation increased phosphorylation of NR2B subunit of NMDA at tyrosine 1472 (pNR2B NMDA) in the hippocampus, but not in the cortex. Similar to behavioral effects norBNI and imipramine, but not SSRIs, blocked NR2B phosphorylation. Moreover, KOR induced depression like behaviors were reversed by NR2B selective inhibitor Ro 25-6981. Mechanistic studies in primary cultured neurons and brain tissues using genetic and pharmacological approaches revealed that stimulation of KOR modulates several molecular correlates of depression. Thus, these findings elucidate molecular mechanism of KOR signaling in treatment resistant depression like behaviors in mice.

How Does Stress-Induced Activation of the Kappa Opioid System Increase Addiction Risk?

How Does Stress-Induced Activation of the Kappa Opioid System Increase Addiction Risk?

Dysregulation of kappa-opioid receptor systems by chronic nicotine modulate the nicotine withdrawal syndrome in an age-dependent manner

Mechanisms that mediate age differences during nicotine withdrawal are unclear. This study compared kappa-opioid receptor (KOR) activation in naïve and nicotine-treated adolescent and adult rats using behavioral and neurochemical approaches to study withdrawal. The behavioral models used to assess withdrawal included conditioned place and elevated plus maze procedures. Deficits in dopamine transmission in the nucleus accumbens (NAcc) were examined using microdialysis procedures. Lastly, the effects of KOR stimulation and blockade on physical signs produced upon removal of nicotine were examined in adults. Nicotine-treated adults displayed a robust aversion to an environment paired with a KOR agonist versus naïve adults. Neither of the adolescent groups displayed a place aversion. KOR activation produced an increase in anxiety-like behavior that was highest in nicotine-treated adults versus all other groups. KOR activation produced a decrease in NAcc dopamine that was largest in nicotine-treated adults versus all other groups. Lastly, KOR activation facilitated physical signs of withdrawal upon removal of nicotine and KOR blockade reduced this effect. Chronic nicotine enhanced the affective, anxiogenic, and neurochemical effects produced by KOR activation in adult rats. Our data suggest that chronic nicotine elicits an increase in KOR function, and this may contribute to nicotine withdrawal since KOR activation facilitated and KOR blockade prevented withdrawal signs upon removal of nicotine. Given that chronic nicotine facilitated the neurochemical effects of KOR agonists in adults but not in adolescents, it is suggested that KOR regulation of mesolimbic dopamine may contribute to age differences in nicotine withdrawal.

Systemic Kappa Opioid Receptor Agonists in the Treatment of Chronic Pruritus: A Literature Review

Chronic pruritus is frequently refractory to currently available treatments. Studies suggest that pruritus may arise from an imbalance of the mu- and kappa-opioid receptor system activity in either the skin or the central nervous system. Stimulation of kappa-opioid receptors by their agonists inhibits pruritus in both animals and humans. The antipruritic effect of kappa-opioid receptors agonists can currently be assumed to be related to their binding to kappa-opioid receptors on keratinocytes and cutaneous and/or central itch neurones. To date, several case reports and 2 controlled trials have demonstrated a beneficial effect of systemic kappa-opioid receptor agonists in the treatment of uraemic pruritus, prurigo nodularis, paraneoplastic and cholestatic pruritus. Nalfurafine hydrochloride (Remitch(®)), a selective kappa-opioid receptor agonist, is approved for the treatment of chronic pruritus in Japan. The aim of this review is to provide an overview of the promising role of kappa- opioid receptors and their agonist in the pathophysiology and treatment of pruritus.

Long-term effects of neonatal stress on adult conditioned place preference (CPP) and hippocampal neurogenesis

Critically ill preterm infants are often exposed to stressors that may affect neurodevelopment and behavior. We reported that exposure of neonatal mice to stressors or morphine produced impairment of adult morphine-rewarded conditioned place preference (CPP) and altered hippocampal gene expression. We now further this line of inquiry by examining both short- and long-term effects of neonatal stress and morphine treatment. Neonatal C57BL/6 mice were treated twice daily from postnatal day (P) 5 to P9 using different combinations of factors. Subsets received saline or morphine injections (2 mg/kg s.c.) or were exposed to our neonatal stress protocol (maternal separation 8 h/d × 5 d + gavage feedings ± hypoxia/hyperoxia). Short-term measures examined on P9 were neuronal fluorojade B and bromodeoxyuridine staining, along with urine corticosterone concentrations. Long-term measures examined in adult mice (>P60) included CPP learning to cocaine reward (±the kappa opioid receptor (KOR) agonist U50,488 injection), and adult hippocampal neurogenesis (PCNA immunolabeling). Neonatal stress (but not morphine) decreased the cocaine–CPP response and this effect was reversed by KOR stimulation. Both neonatal stress or morphine treatment increased hippocampal neurogenesis in adult mice. We conclude that reduced learning and increased hippocampal neurogenesis are both indicators that neonatal stress desensitized mice and reduced their arousal and stress responsiveness during adult CPP testing. Reconciled with other findings, these data collectively support the stress inoculation hypothesis whereby early life stressors prepare animals to tolerate future stress.

Tracking Down the Molecular Substrates of Stress: New Roles for p38α MAPK and Kappa-Opioid Receptors

In this issue, Bruchas etal. (2011) uncover a novel stress-induced p38α MAPK signaling cascade within serotonergic neurons of the dorsal raphe nucleus that mediates depressive and drug-seeking behaviors. Their findings have potentially important implications for medication development.

Interaction between the cardiovascular effects of Clonidine and the κ-opioid agonist U-50,488H in the anterior hypothalamic area of the rat brain

In thiobutabarbitone-anaesthetized rats, microinjection of clonidine (1-40 nmol) into the anterior hypothalamic area (AHy) produced dose-dependent reductions in mean arterial blood pressure and heart rate. Microinjection of the kappa-opioid agonist U-50,488H (3 and 10 nmol) did not modify these parameters. Simultaneous co-administration of clonidine (4 nmol) and U-50,488H (10 nmol) into the AHy resulted in significant potentiation of the clonidine-induced hypotension and marked attenuation of the bradycardia. A lower dose of U-50,488H (3 nmol) co-administered with clonidine (4 nmol) did not influence the cardiovascular responses to clonidine. These findings suggest that AHy neurons involved in the cardiovascular responses to clonidine may be modulated by kappa-opioid receptor stimulation.

Role of kappa opioid receptor in cardioprotection of preconditioning: implications in cardiac surgery.

Kappa-opioid receptor mediates both immediate and delayed cardioprotection of ischemic/metabolic inhibition preconditioning. Both PKC and mitochondria ATP-sensitive K+ channel, mediate the protective action of kappa-opioid receptor stimulation. In delayed cardioprotection, PKC-epsilon may produce its effect via mitochondria ATP-sensitive K+ channel, and a stress inducible heat stress protein 70 may also be involved. Metabolic inhibition causes cell death which is accompanied by Ca2+ overload and mobilization of Ca2+ from sarcoplasmic reticulum to cytoplasm. The altered Ca2+ homeostasis is restored partially by kappa-opioid receptor or metabolic inhibition preconditioning. The finding indicates that opioids such as morphine may be used in the treatment of ischemic heart diseases and in open heart surgery.

Acute withdrawal from chronic escalating-dose binge cocaine administration alters kappa opioid receptor stimulation of [ 35S] guanosine 5′-O-[gamma-thio]triphosphate acid binding in the rat ventral tegmental area

There is evidence that the kappa opioid system plays an important role in cocaine addiction and that chronic cocaine administration and withdrawal from chronic cocaine alter kappa opioid receptor (KOPr) density. The present study employed in situ [ 35S]guanosine 5′-O-[gamma-thio]triphosphate acid (GTPγS) binding autoradiography to measure KOPr-stimulated activation of G-protein in the caudate putamen, nucleus accumbens core and shell, lateral hypothalamus, basolateral amygdala, substantia nigra compacta, substantia nigra reticulata and ventral tegmental area (VTA), in response to chronic cocaine administration or acute and chronic withdrawal from chronic cocaine. Male Fischer rats were injected i.p. with saline or cocaine three times daily at 1 h intervals in an escalating-dose paradigm for 14 days (from 3×15 mg/kg/injection on days 1–3 up to 3×30 mg/kg/injection on days 10–14). Identically treated separate groups were withdrawn from cocaine or saline for 24 h or 14 days. No significant change in KOPr agonist U-69593-stimulated [ 35S]GTPγS was found in the seven regions studied 30 min or 14 days after chronic 14 days escalating-dose binge cocaine administration. However there was an increase in KOPr -stimulated [ 35S]GTPγS binding in the VTA ( P<0.01) of rats withdrawn for 24 h from chronic cocaine. Our results show a cocaine withdrawal induced increase of KOPr signaling in the VTA, and suggest that the KOPr may play a role in acute withdrawal from cocaine.

Ascent of the kappa-opioid receptor in psychopharmacology

Often overshadowed by other members of the endogenous opioid receptor family, kappa-opioid receptors (KORs) are rapidly emerging as an important target for the study and treatment of a variety of central nervous system disorders. This Special Issue is dedicated to 18 papers that describe some of the newest and most important developments. Since the seminal work of Pasternak (1980), there has been great interest in selective KOR agonists for the management of pain. Stimulation of KORs produces analgesia, while the lack of effects at mu-opioid receptors (MORs) minimizes abuse liability. Pain remains a likely indication for KOR agonists (this issue). However, early studies demonstrated that administration of selective KOR agonists to humans elicited unwanted effects including dysphoria, derealization, and depersonalization, some of which can be modeled in animals (this issue). The prominence of these effects has tempered enthusiasm for further development of these agents for clinical use. It is now better understood that MORs and KORs are often located in anatomical apposition within brain areas such as the nucleus accumbens (NAc). As a result of this arrangement, selective activation of these receptor subtypes tends to produce opposite effects on behavior: whereas stimulation of MORs is rewarding, stimulation of KORs causes dysphoria. The work by Negus et al. (this issue) shows that KOR agonists concurrently reduce pain while producing depressive-like behavior, and provides a novel methodology that could be used to screen for novel analgesics with less propensity to affect mood. Chartoff et al. (this issue) use an interesting new ligand, salvinorin A, to provide a potential mechanism by which KOR agonists cause depressive-like behavior: reduction of phasic dopamine release in the NAc. Salvinorin A is of special interest because it is a potent and highly selective KOR agonist that binds to few (if any) other receptors in the brain. Butelman et al. (this issue) and Nemeth et al. (this issue) show how the unique pharmacological profile of salvinorin A can enable new insights on the brain substrates of the types of altered perception that often accompany psychiatric conditions such as schizophrenia. Bruchas and Chavkin (this issue) provide evidence that in addition to their acute dysphoric effects, KOR agonists mimic the cellular effects of stress. The work of Sperling et al. (this issue) implicates the stress-like effects of KORs in increased vulnerability to drugs of abuse including ethanol. Wee and Koob (this issue) describe how KOR stimulation may play a key role in the addiction cycle by influencing processes of positive and negative reinforcement, tying together the ways in which stress, depression, and addiction can interact to control behavior. Until recently, the potential for clinical applications of KOR antagonists seemed limited. These agents were originally envisioned as tools for studies of interactions between agonists and KORs and the functional significance of KORs for behavior, or for understanding receptor– receptor interactions (e.g., dimers). Several papers in this issue suggest that KOR antagonists have potential for broad clinical applicability. As one example, Carr and Lucki (this issue) demonstrate that the KOR antagonist DIPPA has acute anxiolytic-like effects in addition to acute antidepressantW. A. Carlezon Jr. (*) Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, MRC 217, 115 Mill Street, Belmont, MA 02478, USA e-mail: bcarlezon@mclean.harvard.edu

Involvement of kappa opioid receptors in the inhibition of receptor desensitization and PKC activation induced by repeated morphine treatment

Analgesic tolerance to morphine can develop from long-term use of this drug for the treatment of pain. Many reports have shown that stimulation of the kappa opioid receptor (KOR) suppresses development of analgesic tolerance to morphine. Here, we studied the KOR-mediated inhibition of morphine tolerance during repeated morphine treatment, with a focus on desensitization of the receptor. The development of analgesic tolerance to morphine during repeated morphine administration (10 mg kg(-1) s.c.) was completely suppressed by U-50488H (2 mg kg(-1) i.p.), a KOR agonist. The decrease in [35S] GTPgammaS binding activity stimulated by the mu opioid receptor (MOR) agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) was also significantly inhibited by U-50488H. These results indicate that stimulation of KOR caused by repeated morphine treatment either inhibits MOR desensitization or accelerates recycling of MOR on the cell surface, thereby suppressing morphine tolerance. Furthermore, we found that activity of protein kinase C (PKC) was significantly decreased in mice treated with both U-50488H and morphine. These results suggest that the mechanisms underlying KOR-mediated inhibition of analgesic tolerance to morphine may be partly due to suppression of PKC activation and prevention of receptor desensitization.