The long-term effects of stress and kappa opioid receptor activation on conditioned place aversion in male and female California mice

Laman-Maharg, Abigail; Copeland, Tiffany; Sanchez, Evelyn Ordoñes; Campi, Katharine L.; Trainor, Brian C.

doi:10.1016/j.bbr.2017.06.015

Cited by 18 publications

(23 citation statements)

References 50 publications

(78 reference statements)

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“…Sal A has previously been shown to have no aversion in CTA experiments at 0.3 mg/kg [ 72 ], and conditioned place preference at low doses (0.1–40 μg/kg) but aversion at higher doses in rats (0.16–1 mg/kg) [ 105 , 106 ] and in mice (1–3.2 mg/kg) [ 63 ]. While we confirm the aversive properties of U50488 (10 mg/kg) ( Figure 8 a) seen in previous studies [ 104 ], Mesyl Sal B (0.3 mg/kg) had no effects on either place aversion ( Figure 8 b) or taste aversion ( Figure 8 c). Similar results were found for another more potent Sal A analogue, 2-ethoxymethyl ether Sal B (0.1 mg/kg), which did not show aversive effects in the CPA paradigm [ 34 ].…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies have used CPA to measure the aversive properties of the traditional KOPr agonists U69593 [ 101 , 102 , 103 ] and U50488 [ 104 ]. Sal A has previously been shown to have no aversion in CTA experiments at 0.3 mg/kg [ 72 ], and conditioned place preference at low doses (0.1–40 μg/kg) but aversion at higher doses in rats (0.16–1 mg/kg) [ 105 , 106 ] and in mice (1–3.2 mg/kg) [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

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Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents

et al. 2018

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The acute activation of kappa opioid receptors (KOPr) produces antinociceptive and anti-cocaine effects, however, their side-effects have limited further clinical development. Mesyl Sal B is a potent and selective KOPr analogue of Salvinorin A (Sal A), a psychoactive natural product isolated from the plant Salvia divinorum. We assessed the antinociceptive, anti-cocaine, and side-effects of Mesyl Sal B. The anti-cocaine effects are evaluated in cocaine-induced hyperactivity and behavioral sensitization to cocaine in male Sprague Dawley rats. Mesyl Sal B was assessed for anhedonia (conditioned taste aversion), aversion (conditioned place aversion), pro-depressive effects (forced swim test), anxiety (elevated plus maze) and learning and memory deficits (novel object recognition). In male B6.SJL mice, the antinociceptive effects were evaluated in warm-water (50 °C) tail withdrawal and intraplantar formaldehyde (2%) assays and the sedative effects measured with the rotarod performance task. Mesyl Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity and behavioral sensitization to cocaine without modulating sucrose self-administration and without producing aversion, sedation, anxiety, or learning and memory impairment in rats. However, increased immobility was observed in the forced swim test indicating pro-depressive effects. Mesyl Sal B was not as potent as Sal A at reducing pain in the antinociceptive assays. In conclusion, Mesyl Sal B possesses anti-cocaine effects, is longer acting in vivo and has fewer side-effects when compared to Sal A, however, the antinociceptive effects are limited.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents

et al. 2018

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“…First, the overwhelming majority of preclinical studies on KOR antagonists have been conducted in male rodents (but see, Russell et al, 2014 ), so it is unclear whether these antagonists have similar properties in females. This is an essential question because women are almost twice as likely to develop depression as men ( Kessler, 2003 ), and sex differences in physiological responses to stress may affect risk for depression ( Bale and Epperson, 2015 ; Laman-Maharg et al, 2017 ). Second, most studies have focused on the short-term effects of KOR antagonists in stressful contexts.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, social defeat stress induces KOR activation ( McLaughlin et al, 2006 ) and has been reported to increase time spent immobile in some cases ( Jin et al, 2015 ) but not others ( Krishnan et al, 2007 ). There is growing evidence that over a period of days or weeks, stressors such as defeat reduce the efficacy of KOR on behavior ( Al-Hasani et al, 2013 ; Laman-Maharg et al, 2017 ). Overall, while there is strong evidence that KOR antagonists have antidepressant-like effects in the force swim, the extent to which this effect generalizes to females or to females that have experienced stress is unclear.…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in the Effects of a Kappa Opioid Receptor Antagonist in the Forced Swim Test

et al. 2018

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There is growing evidence that kappa opioid receptor (KOR) antagonists could be a useful class of therapeutics for treating depression and anxiety. However, the overwhelming majority of preclinical investigations examining the behavioral effects of KOR antagonists have been in male rodents. Here, we examined the effects of the long-acting KOR antagonist nor-binaltophimine (norBNI) on immobility in the forced swim test in males and females of two different rodent species (C57Bl/6J and California mice). Consistent with previous reports, norBNI (10 mg/kg) decreased immobility in the forced swim test for male C57Bl/6J and California mice. Surprisingly, dose–response studies in female C57Bl/6J and California mice showed that norBNI did not reduce immobility. Pharmacokinetic analyses showed that metabolism and brain concentrations of norBNI were similar in male and female C57Bl/6J. In the nucleus accumbens of male but not female C57Bl/6J, norBNI increased phosphorylation of c-Jun N-terminal kinase (pJNK), a putative mechanism for norBNI action. However, no differences in pJNK were observed in male or female California mice. Together, these results suggest that immobility in the forced swim test is less dependent on endogenous KOR signaling in female rodents and highlight the importance of examining the effects of possible therapeutic agents in both males and females.

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“…All drugs were dissolved in 100% DMSO and diluted in saline to the desired concentration (no DMSO concentration exceeded 5% v/v final). In drug combination experiments, nalfurafine was injected subcutaneously (sc) as described in the limited literature available regarding this compound's use in mice (Endoh et al, 1999;, while U50,488 and morphine were delivered by intraperitoneal (ip) injection as commonly described (Rada et al, 1996;McLaughlin et al, 2006;Koo et al, 2012;Muschamp et al, 2012;Laman-Maharg et al, 2017;Robinson et al, 2017). Dose range for nalfurafine and U50,488 were chosen based upon the place preference data in the literature Land et al, 2009b;Ehrich et al, 2015b).…”

Section: -Drugsmentioning

confidence: 99%

Genetic and Pharmacologic Studies Towards Prevention of opioid use disorder

Kaski¹

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Genetic and Pharmacologic Studies Towards Prevention of opioid use disorder Shane West Kaski Endogenous opioids mediate both analgesic and affective responses to stress. While the mu opioid receptor (MOR) produces the reinforcing euphoric effects responsible for the high abuse potential of traditional opioid analgesics, the kappa opioid receptor (KOR) is hypothesized to mediate the dysphoric component of stress. With increasing rates of opioid addiction, extensive research efforts are focused on better understanding each of these systems and how they interact, with the goal of developing less addictive pain management strategies and better approaches to addiction treatment. With this in mind, we conducted both clinical and preclinical studies aimed at developing better treatment strategies for opioid use and the management of patients with opioid use disorder (OUD). First, we assessed a local cohort of patients with (OUD) for a collection of single nucleotide polymorphisms (SNPs) related to reward processing, with the goal of furthering efforts to develop a gene-based screening mechanism for OUD risk assessment. Second, we conducted preclinical assessments of the G protein-biased KOR agonist nalfurafine as a potential adjuvant medication for increasing the therapeutic efficacy of opioid-based analgesia. Genetic analysis of OUD patients identified two SNPs within the gene encoding the mu opioid receptor, one SNP within the gene encoding the serotonin 2B (5-HT2B) receptor, and one SNP within the gene encoding Regulator of G protein Signaling 2 (RGS2), with the frequency of each SNP varying significantly from that observed in reference populations of European descent. Preclinical investigations with nalfurafine use in mice demonstrated a greater analgesic synergy when co-administered with morphine than morphine co-administered with the unbiased KOR agonist U50,488. As G protein-biased KOR agonists are hypothesized to produce less dysphoria (a therapeutically limiting side effect of KOR agonists), they may present a viable method for reducing the dose of MOR-targeting analgesic necessary for adequate pain relief, thereby reducing the likelihood of developing OUD. Further research is necessary to identify any antitherapeutic effects of co-administering these two classes of drugs, as well as the range of pain modalities for which this approach is efficacious.

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The long-term effects of stress and kappa opioid receptor activation on conditioned place aversion in male and female California mice

Cited by 18 publications

References 50 publications

Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents

Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents

Sex Differences in the Effects of a Kappa Opioid Receptor Antagonist in the Forced Swim Test

Genetic and Pharmacologic Studies Towards Prevention of opioid use disorder

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