Estrogen Modulation of Morphine Analgesia of Visceral Pain in Female Rats Is Supraspinally and Peripherally Mediated

Ji, Yaping; Murphy, Anne Z.; Traub, Richard J.

doi:10.1016/j.jpain.2007.01.006

Cited by 49 publications

(41 citation statements)

References 41 publications

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“…in female rats (5,23,24,56). Quantifying the serum levels of estradiol in the intact female rat just before electrophysiological study of acutely isolated myelinated Ah-type VGN may help determine whether the excitability of this unique subtype of vagal afferents from intact female rat is associated with the phase of the estrous cycle.…”

Section: Discussionmentioning

confidence: 99%

17β-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats

Qiao

et al. 2009

American Journal of Physiology-Cell Physiology

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Qiao GF, Li BY, Lu YJ, Fu YL, Schild JH. 17␤-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats. Am J Physiol Cell Physiol 297: C654 -C664, 2009. First published July 1, 2009 doi:10.1152/ajpcell.00059.2009.-We recently identified a myelinated vagal afferent subpopulation (Ah type) far more prevalent in female than male rats and showed that this difference extends to functionally specific visceral sensory afferents, baroreceptors of the aortic arch. Excitability of myelinated Ah-type afferents is markedly reduced after ovariectomy (OVX). Here we tested the hypothesis that 17␤-estradiol can selectively restore excitability of these sex-specific vagal afferents. Acutely isolated vagal afferent neurons (VGN) from intact and OVX adult female rats were used with patch-clamp technique and current-clamp protocols to assess the effect of acute application of 17␤-estradiol on neuronal excitability. At over physiologically relevant 17␤-estradiol concentrations for rat (1-10 nM) excitability of myelinated Ah-type vagal afferents is restored to discharge frequencies comparable to those in intact females, albeit with some interesting differences related to burst and sustained patterns of neuronal discharge. Restoration of excitability occurs within 3 min of hormone application and is stereo specific, because 1,000 nM 17␣-estradiol fails to alter excitability. Furthermore, activation of G protein-coupled estrogen receptor GPR30 with highly selective agonist G-1 similarly restores excitability of Ah-type afferents. The effectiveness of 17␤-estradiol and G-1 is completely eliminated by application of high-affinity estrogen receptor ligand ICI-182,780. 17␤-Estradiol conjugated with BSA is ϳ70% as effective as 17␤-estradiol alone in restoring Ah-type VGN excitability. These data support our conclusions that the cellular mechanisms leading to rapid restoration of neuronal excitability of myelinated Ah-type VGN after OVX occur, at least in part, via membrane-bound estrogen receptors. We contend that recovery of high-frequency discharge at physiologically relevant 17␤-estradiol concentrations implies that this unique subtype of low-threshold myelinated vagal afferent may account for some of the sex-related differences in visceral organ system function. Sex differences in cardiovascular and gastrointestinal function and the potential role of GPR30 in modulation of sex-specific myelinated Ah-type vagal afferents are discussed. sensory afferent; visceral afferent; estrogen receptor; GPR30; ovariectomy VISCERAL AFFERENTS with cell bodies in the vagal ganglia innervate a functionally diverse range of organs associated with the cardiovascular, gastrointestinal, and pulmonary systems. Vagal afferent mediation of the reflexogenic properties of the autonomic nervous system (ANS) in addition to visceral sensation is well recognized (for review see Ref. 55). Because the peripheral sensory terminals can be influenced by a wide range of endogenous chemicals released as a consequenc...

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Section: Discussionmentioning

confidence: 99%

17β-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats

Qiao

et al. 2009

American Journal of Physiology-Cell Physiology

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“…Sex differences in morphine analgesia have been demonstrated in multiple preclinical studies employing both acute and persistent orofacial (Okamoto et al, 2005), visceral (Ji et al ., 2006; 2007) and somatic (Bartok & Craft, 1997; Cicero et al ., 1997; Boyer et al ., 1998; Kest et al ., 1999; Barrett et al ., 2001; Cook & Nickerson, 2005; Wang et al ., 2006) pain models, with ED 50 values two times higher in female compared to male rats (Wang et al ., 2006; Ji et al ., 2007). Importantly, sex differences in opiate sensitivity are not due to the pharmacokinetics of morphine as no sex difference has been reported in serum or brain levels of morphine; and elimination and metabolic rates are comparable between sexes (Cicero et al ., 1996; Craft et al ., 1996; Cicero et al ., 1997; Sarton et al ., 2000).…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in μ-Opioid Receptor Expression in the Rat Midbrain Periaqueductal Gray Are Essential for Eliciting Sex Differences in Morphine Analgesia

Loyd¹,

Wang²,

Murphy³

2008

J. Neurosci.

163

136

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Opioid-based narcotics are the most widely prescribed therapeutic agent for the alleviation of persistent pain; however, it is becoming increasingly clear that morphine is significantly less potent in women compared with men. Morphine primarily binds to -opioid receptors (MORs), and the periaqueductal gray (PAG) contains a dense population of MOR-expressing neurons. Via its descending projections to the rostral ventromedial medulla and the dorsal horn of the spinal cord, the PAG is considered an essential neural substrate for opioid-based analgesia. We hypothesized that MOR expression in the PAG was sexually dimorphic, and that these sex differences contribute to the observed sex differences in morphine potency. Using immunohistochemistry, we report that males had a significantly higher expression of MOR in the ventrolateral PAG compared with cycling females, whereas the lowest level of expression was observed in proestrus females. CFA-induced inflammatory pain produced thermal hyperalgesia in both males and females that was significantly reversed in males with a microinjection of morphine into the ventrolateral PAG; this effect was significantly greater than that observed in proestrus and estrus females. Selective lesions of MOR-expressing neurons in the ventrolateral PAG resulted in a significant reduction in the effects of systemic morphine in males only, and this reduction was positively correlated with the level of MOR expression in the ventrolateral PAG. Together, these results provide a mechanism for sex differences in morphine potency.

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“…MPOA plays a key role in neuroendocrine and gonado-steroidal regulation and reproductive behaviors [4,10,16,22,26,34]. There are sex differences in nociceptive processing and analgesia, and changes in nociceptive thresholds and opioid-mediated analgesia occur during the estrus cycle, steroid hormone administration, and reproductive activities [7,17,19,31,35,36]. The medial preoptic nucleus (MPN), the sexually dimorphic component of MPOA, contains neurons that express estrogen or androgen receptors and project to PAG [25].…”

Section: Discussionmentioning

confidence: 99%

“…Previous work has demonstrated sex differences as well as effects of steroid hormones on nociception and responses to analgesics [7,17,19,31,35,36]. The MPOA is a sexually dimorphic structure that contains large populations of neurons that concentrate gonadal hormones and express estrogen and androgen receptors [25].…”

Section: Introductionmentioning

confidence: 99%

Inactivation of the periaqueductal gray attenuates antinociception elicited by stimulation of the rat medial preoptic area

Zhang¹,

Ennis²

2007

Neuroscience Letters

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The medial preoptic area (MPOA) is a sexually dimorphic structure that plays key roles in gonadosteroidal regulation and thermoregulation. The MPOA may be involved in sex-based differences in nociceptive processing and steroid hormones effect on pain thresholds. Consistent with this, there is evidence that MPOA can produce antinociception or hyperalgesia. MPOA stimulation inhibits spinal cord or trigeminal neuronal responses to noxious stimuli or produces analgesia, yet most of these studies utilized electrical stimulation which antidromically activates periaqueductal gray (PAG) and rostroventromedial medulla (RVM) neurons involved in descending modulation of nociception. Effects of selective activation of MPOA neurons on behavioral indices of antinociception and the site-specificity of such responses are unknown. To address these questions, we examined the influence of MPOA microinjections of d, l homocysteate (DLH) on hindlimb and tail nocifensive reflexes in lightly anesthetized rats. DLH, but not saline, microinjections into several MPOA subregions markedly increased withdrawal response latencies to noxious thermal stimuli. Antinociceptive effects of MPOA activation were abolished by microinjection of lidocaine into PAG. These results suggest that activation of MPOA neurons produces antinociception that is at least partly mediated by projections to PAG.

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Estrogen Modulation of Morphine Analgesia of Visceral Pain in Female Rats Is Supraspinally and Peripherally Mediated

Cited by 49 publications

References 41 publications

17β-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats

17β-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats

Sex Differences in μ-Opioid Receptor Expression in the Rat Midbrain Periaqueductal Gray Are Essential for Eliciting Sex Differences in Morphine Analgesia

Inactivation of the periaqueductal gray attenuates antinociception elicited by stimulation of the rat medial preoptic area

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