Pleiotropic Opioid Regulation of Spinal Endomorphin 2 Release and Its Adaptations to Opioid Withdrawal Are Sexually Dimorphic

Chakrabarti, Swapan; Liu, Nai-Jiang; Zadina, James E.; Sharma, Tarak R.; Gintzler, Alan R.

doi:10.1124/jpet.111.186874

Cited by 16 publications

(28 citation statements)

References 30 publications

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“…This was attributed to increased βAR-Gs coupling because there was no difference in βAR affinity or number and responses to forskolin or GTP-γ-S were comparable between male and female hepatocytes [54]. Sex differences in μ-opioid receptor (MOR) coupling to G-proteins have been suggested to play a role in differential adaptation to opiate withdrawal in the spinal cord [55]. Here the release of the potent endogeous opioid, endomorphin 2, is regulated by MOR, which inhibits release through a Gi-protein coupled mechanism.…”

Section: Sex Biased Signaling Of Other Receptorsmentioning

confidence: 99%

Sex-specific cell signaling: the corticotropin-releasing factor receptor model

Valentino

Bockstaele

Bangasser

2013

Trends in Pharmacological Sciences

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Elucidating the biological basis for sex differences in diseases can reveal their pathophysiology and guide the development of individualized treatments. Here we review evidence for the novel concept that receptor signaling can be sex biased such that the specific pathways engaged by ligand binding are determined by sex. As an example, this review focuses on the receptor for corticotropin-releasing factor (CRF), a stress-related peptide implicated in diverse psychiatric and medical disorders that are more prevalent in females. There is evidence for sex biases in CRF receptor coupling to G-proteins and β-arrestin that render females more sensitive to acute stress and less able to adapt to chronic stress. Taken with evidence for sex biased signaling in other receptor systems, the studies demonstrate the broad potential impact of this characteristic in determining sex differences in disease and therapeutic efficacy and underscore the importance of studying females in medical and pharmacological research.

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Section: Sex Biased Signaling Of Other Receptorsmentioning

confidence: 99%

Sex-specific cell signaling: the corticotropin-releasing factor receptor model

Valentino

Bockstaele

Bangasser

2013

Trends in Pharmacological Sciences

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“…The release of the endogenous opioid, endomorphin 2 (EM2), is regulated by both positive and negative feedback systems that are activated following the binding of EM2 to μOR autoreceptors in the spinal cord. In males, the activated μOR can couple with either Gs or Gi/o, which respectively enhance and inhibit subsequent EM2 release [387]. Under normal conditions, the negative feedback pathway predominates; however, following morphine withdrawal, compensatory mechanisms kick in that shift the balance towards favoring Gs coupling and enhanced EM2 release.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis

2012

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In this review we propose that there are sex differences in how men and women enter onto the path that can lead to addiction. Males are more likely than females to engage in risky behaviors that include experimenting with drugs of abuse, and in susceptible individuals, they are drawn into the spiral that can eventually lead to addiction. Women and girls are more likely to begin taking drugs as self-medication to reduce stress or alleviate depression. For this reason women enter into the downward spiral further along the path to addiction, and so transition to addiction more rapidly. We propose that this sex difference is due, at least in part, to sex differences in the organization of the neural systems responsible for motivation and addiction. Additionally, we suggest that sex differences in these systems and their functioning are accentuated with addiction. In the current review we discuss historical, cultural, social and biological bases for sex differences in addiction with an emphasis on sex differences in the neurotransmitter systems that are implicated.

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“…sufentanil augmented spinal EM2 release contrasts with our previous finding that MOR-mediated modulation of neurotransmitter release and intracellular signaling in vitro is bimodal, with stimulatory (G s -mediated) and inhibitory (G i -mediated) effects occurring at low and high concentrations of MOR agonist, respectively. 10,34,36,95,99 Multiple factors could account for the current ability of a seemingly high dose of i.t. sufentanil to facilitate EM2 release: (1) An i.t.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that sufentanil enhances in vitro K + -induced release of EM2, an effect that was observable only following in vitro pretreatment with pertussis toxin 10 to eliminate MOR-mediated inhibition of K + -induced EM2 release. 10,36 However, the contribution of endogenous EM2 to spinal antinociception resulting from intrathecally administered MOR agonists, and the mechanisms thereof, were not studied. Such knowledge could hold a key to harnessing endogenous opioids for pain management.…”

Section: Introductionmentioning

confidence: 98%

Contribution of Endogenous Spinal Endomorphin 2 to Intrathecal Opioid Antinociception in Rats Is Agonist Dependent and Sexually Dimorphic

Kumar

Liu

Madia

et al. 2015

The Journal of Pain

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Interactions between exogenous and endogenous opioids are not commonly investigated as a basis for sexually dimorphic opioid analgesia. We investigated the influence of spinal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, on the spinal antinociception produced by intrathecally administered opioids. Activation of spinal MORs facilitated spinal EM2 release. This effect was sexually dimorphic, occurring in males but not females. Although activational effects of testosterone were required for opioid facilitation of spinal EM2 release in males, the absence of this facilitation in females resulted from neither insufficient levels of testosterone nor mitigating effects of estrogens. Strikingly, in males, the contribution of spinal EM2 to the analgesia produced by intrathecally applied MOR agonists depended on their analgesic efficacy relative to that of EM2. Spinal EM2 released by the higher efficacy MOR agonist sufentanil diminished sufentanil’s analgesic effect, whereas EM2 released by the lower efficacy morphine had the opposite effect on spinal morphine antinociception. Understanding antithetical contributions of endogenous EM2 to intrathecal opioid antinociception not only enlightens the selection of opioid medications for pain management, but also helps explain variable sex-dependence of the antinociception produced by different opioids, facilitating the acceptance of sexually dimorphic antinociception as a basic tenet. Perspective The male-specific MOR-coupled enhancement of spinal EM2 release implies a parallel ability to harness endogenous EM2 antinociception. The inferred diminished ability of females to utilize the spinal EM2 antinociceptive system could contribute to their greater frequency and severity of chronic pain syndromes.

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Pleiotropic Opioid Regulation of Spinal Endomorphin 2 Release and Its Adaptations to Opioid Withdrawal Are Sexually Dimorphic

Cited by 16 publications

References 30 publications

Sex-specific cell signaling: the corticotropin-releasing factor receptor model

Sex-specific cell signaling: the corticotropin-releasing factor receptor model

Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis

Contribution of Endogenous Spinal Endomorphin 2 to Intrathecal Opioid Antinociception in Rats Is Agonist Dependent and Sexually Dimorphic

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