Sex differences in kappa opioid receptor antinociception is influenced by the number of X chromosomes in mouse

Taylor, Austin L.; Chadwick, Caylin; Mehrabani, Sadaf; Hrncir, Haley; Arnold, Arthur P.; Evans, Christopher J.

doi:10.1002/jnr.24704

Cited by 17 publications

(6 citation statements)

References 33 publications

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“…Female rats exhibited hyperalgesia to subanalgesic doses of morphine, whereas males did not ( Holtman and Wala, 2005 ). Evidence also indicates genomic-dependent ( Taylor et al, 2020 ) and hormone-dependent KOR-mediated effects in female rats and mice ( Rasakham and Liu-Chen, 2011 ; Abraham et al, 2018 ). Moreover, as recently highlighted by Becker and Chartoff (2019) , we still have very limited knowledge of the role of sex, genetic, epigenetic, and pharmacological mechanisms that are associated with KOR function.…”

Section: Introductionmentioning

confidence: 99%

κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats

Marchette

Gregory-Flores

Tunstall

et al. 2021

Neurobiology of Stress

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Although opioids are potent analgesics, a consequence of chronic opioid use is hyperalgesia during withdrawal, which may contribute to opioid misuse. Dynorphin, the endogenous ligand of κ-opioid receptors (KORs), is upregulated in opioid-dependent rats and in animal models of chronic pain. However, the role of KORs in opioid withdrawal-induced hyperalgesia remains to be determined. We hypothesized that KOR antagonism would reverse opioid withdrawal-induced hyperalgesia in opioid-dependent rats. Male and female Wistar rats received daily injections of heroin (2–6 mg/kg, SC) and were tested for mechanical sensitivity in the electronic von Frey test 4–6 h into withdrawal. Female rats required significantly more heroin than male rats to reach comparable levels of both heroin-induced analgesia and hyperalgesia (6 mg/kg vs. 2 mg/kg). Once hyperalgesia was established, we tested the effects of the KOR antagonists nor-binaltorphimine (norBNI; 30 mg/kg, SC) and 5′-guanidinonaltrindole (5′GNTI; 30 mg/kg, SC). When the animals continued to receive their daily heroin treatment (or saline treatment in the repeated saline group) five times per week throughout the experiment, both KOR antagonists reversed heroin withdrawal-induced hyperalgesia. The anti-hyperalgesia effect of norBNI was more prolonged in males than in females (14 days vs. 7 days), whereas 5′GNTI had more prolonged effects in females than in males (14 days vs. 4 days). The behavioral effects of 5′GNTI coincided with higher 5′GNTI levels in the brain than in plasma when measured at 24 h, whereas 5′GNTI did not reverse hyperalgesia at 30 min posttreatment when 5′GNTI levels were higher in plasma than in the brain. Finally, we tested the effects of 5′GNTI on naloxone-induced and spontaneous signs of opioid withdrawal and found no effect in either male or female rats. These findings indicate a functional role for KORs in heroin withdrawal-induced hyperalgesia that is observed in rats of both sexes.

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Section: Introductionmentioning

confidence: 99%

κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats

Marchette

Gregory-Flores

Tunstall

et al. 2021

Neurobiology of Stress

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“…2a,d), consistent with previous reports for this and related standard KOR agonists. 26,27 . In contrast, oxa-noribogaine shows a small rightward shift in the tail-flick assay in one cohort (ED 50(male) = 3.0 mg/kg to ED 50(female) = 4.9 mg/kg, Fig.…”

Section: Oxa-noribogaine Shows Potent Analgesia No Aversion and No Pr...mentioning

confidence: 99%

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Use

Havel

Kruegel

Bechand

et al. 2021

Preprint

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Substance use and related mental health epidemics are causing increasing suffering and death in diverse communities. Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, currently approved medications do not reverse the persistent neurocircuitry and psychological changes that underlie addiction states, highlighting an urgent need for radically different therapeutic approaches. Ibogaine provides an important drug prototype in this direction, as a psychoactive iboga alkaloid suggested to have the ability to interrupt maladaptive habits including opioid use in drug-dependent humans. However, ibogaine and its major metabolite noribogaine present considerable safety risk associated with cardiac arrhythmias. We introduce a new class of iboga alkaloids - "oxa-iboga" - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds act as potent kappa opioid receptor agonists in vitro and in vivo but exhibit atypical behavioral features compared to standard kappa psychedelics. We show that oxa-noribogaine has greater therapeutic efficacy in addiction models and no cardiac pro-arrhythmic potential, compared to noribogaine. Oxa-noribogaine induces long-lasting suppression of morphine intake after a single dose in rat models of addiction and persistent reduction of morphine intake after a short treatment regimen. Oxa-noribogaine maintains and enhances the ability of iboga compounds to effect lasting alteration of addiction-like states while addressing iboga's cardiac liability. As such, oxa-iboga compounds represent candidates for a new kind of anti-addiction pharmacotherapeutics.

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“…In this model, sex chromosome effects on phenotypes are measured by comparing XX and XY mice with the same type of gonad (either testes or ovaries), and hormone effects on any phenotype are measured by comparing mice with different types of gonads but with the same type of sex chromosomes (either XX or XY). Use of FCG mice has led to the novel discovery of sex chromosome effects that contribute to sex differences in body weight and adiposity, autoimmune disease, Alzheimer's disease, numerous cardiovascular diseases, neural tube closure defects, and the brain and behavior [8][9][10][11][12][13][14][15][16]. Use of FCG mice confirmed gonadal hormonal control of other sex differences [2,14,17,18] A significant limitation is that the FCG model has only been available in mice.…”

Section: Introductionmentioning

confidence: 99%

A “Four Core Genotypes” rat model to distinguish mechanisms underlying sex-biased phenotypes and diseases

Arnold¹,

Chen²,

Grzybowski³

et al. 2023

Preprint

Self Cite

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Background: We have generated a rat model similar to the Four Core Genotypes mouse model, allowing comparison of XX and XY rats with the same type of gonad. The model detects novel sex chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype. Methods: XY rats were produced with an autosomal transgene of Sry, the testis-determining factor gene, which were fathers of XX and XY progeny with testes. In other rats, CRISPR-Cas9 technology was used to remove Y chromosome factors that initiate testis differentiation, producing fertile XY gonadal females that have XX and XY progeny with ovaries. These groups can be compared to detect sex differences caused by sex chromosome complement (XX vs. XY) and/or by gonadal hormones (rats with testes vs. ovaries). Results: We have measured numerous phenotypes to characterize this model, including gonadal histology, breeding performance, anogenital distance, levels of reproductive hormones, body and organ weights, and central nervous system sexual dimorphisms. Serum testosterone levels were comparable in adult XX and XY gonadal males. Numerous phenotypes previously found to be sexually differentiated by the action of gonadal hormones were found to be similar in XX and XY rats with the same type of gonad, suggesting that XX and XY rats with the same type of gonad have comparable levels of gonadal hormones at various stages of development. Conclusion: The results establish a powerful new model to discriminate sex chromosome and gonadal hormone effects that cause sexual differences in rat physiology and disease.

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Sex differences in kappa opioid receptor antinociception is influenced by the number of X chromosomes in mouse

Abstract: Activation of the kappa opioid receptor (KOR) produces analgesia without euphoria and is emerging as a target for chronic pain and itch without abuse potential. The KOR system is also notable for a significant sex difference, with females less responsive to KOR agonists than males

Cited by 17 publications

References 33 publications

κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats

κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Use

A “Four Core Genotypes” rat model to distinguish mechanisms underlying sex-biased phenotypes and diseases

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