Sex differences in the anatomical and functional organization of the periaqueductal gray‐rostral ventromedial medullary pathway in the rat: A potential circuit mediating the sexually dimorphic actions of morphine

Loyd, Dayna R.; Murphy, Anne Z.

doi:10.1002/cne.20962

Cited by 110 publications

(109 citation statements)

References 119 publications

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“…As reported previously (Loyd & Murphy, 2006), there were significantly more retrogradely labeled neurons across all rostrocaudal levels of the PAG in female as compared to male rats [F (1,216) = 48.2, p < 0.0001]. Acute systemic administration of morphine induced Fos labeling in a subset of PAG output neurons in both male and female rats.…”

Section: Sexually Dimorphic Activation Of the Pag-rvm Circuit By Morpsupporting

confidence: 78%

“…Interestingly, persistent inflammatory pain only activates this pathway in males. Similarly, systemic morphine administration decreases noxious stimulus-induced activation of the PAG in male but not female rats (Loyd and Murphy, 2006). Together, these studies suggest a sexually dimorphic action of morphine within the PAG.…”

mentioning

confidence: 70%

“…Briefly, sections were rinsed extensively in potassium phosphate-buffered saline (KPBS) to remove cryoprotectant solution immediately followed by a 20-minute incubation in 1% sodium borohydride to remove excess aldehydes. The tissue was then incubated in primary antibody solution(s) previously described (Loyd and Murphy, 2006): rabbit anti-Fos (Oncogene; Cambridge, MA, lot no. 4194; 1:50,000) and/or rabbit anti-FG (Chemicon; Billerica, MA, lot no.…”

Section: Immunocytochemistrymentioning

confidence: 99%

“…Neurons were counted in two PAG subdivisions: dorsomedial and lateral/ventrolateral; these subdivisions are clearly distinguishable based on the distribution of retrograde labeling from the RVM (van Bockstaele et al, 1991,Bandler andShipley, 1994). The lateral/ ventrolateral region was counted unilaterally as there are no differences in the number of FG + cells for the left versus right side of PAG (Loyd and Murphy, 2006). There are no cytoarchitectural or anatomical boundaries between the lateral and ventrolateral regions; therefore, these regions were counted together to avoid experimenter bias.…”

mentioning

confidence: 99%

“…The tissue was sectioned at 25μm so that 125μm separates each analyzed level of the PAG thus avoiding any bias of counting the same cell twice. Additionally, previous data has shown that there are no sex differences in the mean area (mm 2 ) of PAG between weight-matched male and female Sprague-Dawley rats (Loyd and Murphy, 2006). Data are expressed as the mean ± standard error of the mean (SEM) from which percentages were calculated.…”

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confidence: 99%

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Morphine preferentially activates the periaqueductal gray–rostral ventromedial medullary pathway in the male rat: A potential mechanism for sex differences in antinociception

2007

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The midbrain periaqueductal gray (PAG), and its descending projections to the rostral ventromedial medulla (RVM), provides an essential neural circuit for opioid-produced antinociception. Recent anatomical studies have reported that the projections from the PAG to the RVM are sexually dimorphic and that systemic administration of morphine significantly suppresses pain-induced activation of the PAG in male but not female rats. Given that morphine antinociception is produced in part by disinhibition of PAG output neurons, it is hypothesized that a differential activation of PAG output neurons mediates the sexually dimorphic actions of morphine. The present study examined systemic morphine-induced activation of PAG-RVM neurons in the absence of pain. The retrograde tracer fluorogold (FG) was injected into the RVM to label PAG-RVM output neurons. Activation of PAG neurons was determined by quantifying the number of Fos-positive neurons one hour following systemic morphine administration (4.5 mg/kg). Morphine produced comparable activation of the PAG in both male and female rats, with no significant differences in either the quantitative or qualitative distribution of Fos. While microinjection of FG into the RVM labeled significantly more PAG output neurons in female rats than male rats, very few of these neurons (20%) were activated by systemic morphine administration in comparison to males (50%). The absolute number of PAG-RVM neurons activated by morphine was also greater in males. These data demonstrate widespread disinhibition of PAG neurons following morphine administration. The greater morphine-induced activation of PAG output neurons in male compared to female rats is consistent with the greater morphine-induced antinociception observed in males. Keywordspain; morphine analgesia; pain inhibition; opioid; sexual dimorphism endogenous descending pathway Morphine and other mu-opioid receptor agonists are the most effective pharmacological treatment for the alleviation of persistent pain. However, it is becoming increasingly clear that morphine does not produce the same degree of analgesia in males and females. In the majority of studies reported to date, morphine produced a greater antinociceptive response in males in Correspondence to: Anne Z. Murphy, Ph.D., Dept. Biology, Center for Behavioral Neuroscience, Georgia State University, PO Box 4010, Atlanta, amurphy@gsu.edu, Phone: 404.463.9661, Fax: 404.651.2509 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Bodnar et al., 1988,Craft, 2003b,Craft, 2003a,Cook and Nickerson, 2005,Wang et al., 2006. Sex difference...

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Section: Sexually Dimorphic Activation Of the Pag-rvm Circuit By Morpsupporting

confidence: 78%

mentioning

confidence: 70%

Section: Immunocytochemistrymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Morphine preferentially activates the periaqueductal gray–rostral ventromedial medullary pathway in the male rat: A potential mechanism for sex differences in antinociception

2007

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Nucleus paragigantocellularis afferents in male and female rats: Organization, gonadal steroid receptor expression, and activation during sexual behavior

Normandin

Murphy

2008

J of Comparative Neurology

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The supraspinal regulation of genital reflexes is poorly understood. The brainstem nucleus paragigantocellularis (nPGi) of rats is a well-established source of tonic inhibition of genital reflexes. However, the organization, gonadal steroid receptor expression, and activity of nPGi afferents during sex have not been fully characterized in male and female rats. To delineate the anatomical and physiological organization of nPGi afferents, the retrograde tracer Fluoro-Gold (FG) was injected into the nPGi of sexually experienced male and female rats. Animals engaged in sexual behavior 1 hour before sacrifice. Cells containing FG, estrogen receptor-alpha (ER(alpha)), androgen receptor (AR), and the immediate-early gene product Fos were identified immunocytochemically. Retrograde labeling from the nPGi was prominent in the bed nucleus of the stria terminalis, paraventricular nucleus (PVN), posterior hypothalamus, precommissural nucleus, deep mesencephalic nucleus, and periaqueductal gray (PAG) of both sexes. Sex differences were observed in the caudal medial preoptic area (MPO), with significantly more FG+ cells observed in males, and in the PAG and inferior colliculus, where significantly more FG+ cells were observed in females. The majority of regions that contained FG+ cells also contained ER(alpha) or AR, indicating sensitivity to gonadal steroids. The proportions of FG+ cells that co-localized with sex-induced Fos was high in the PVN of both sexes and high in the MPO of males but low in the PAG of both sexes despite the large number of PAG-nPGi output neurons and Fos+ cells in both sexes. The characterization of these afferents will lead to a further understanding of the neural regulation of genital reflexes.

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Increased neuronal expression of neurokinin‐1 receptor and stimulus‐evoked internalization of the receptor in the rostral ventromedial medulla of the rat after peripheral inflammatory injury

Hamity

Walder

Hammond

2014

J of Comparative Neurology

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This study examined possible mechanisms by which Substance P (Sub P) assumes a pronociceptive role in the rostral ventromedial medulla (RVM) under conditions of peripheral inflammatory injury, in this case produced by intraplantar (ipl) injection of complete Freund’s adjuvant (CFA). In saline- and CFA-treated rats, neurokinin-1 receptor (NK1R) immunoreactivity was localized to neurons in the RVM. Four days after ipl injection of CFA, the number of NK1R immunoreactive neurons in the RVM was increased by 30%, and there was a concomitant increase in NK1R immunoreactive processes in CFA-treated rats. Although NK1R immunoreactivity was increased, tachykinin-1 receptor (Tacr1) mRNA was not increased in the RVM of CFA-treated rats. To assess changes in Sub P release, the number of RVM neurons that exhibited NK1R internalization was examined in saline- and CFA-treated rats following noxious heat stimulation of the hind paws. Only CFA-treated rats that experienced noxious heat stimulation exhibited a significant increase in the number of neurons showing NK1R internalization. These data suggest that tonic Sub P release is not increased as a simple consequence of peripheral inflammation, but that phasic or evoked release of Sub P in the RVM is increased in response to noxious peripheral stimulation in a persistent inflammatory state. These data support the proposal that an upregulation of the NK1R in the RVM, as well as enhanced release of Sub P following noxious stimulation underlie the pronociceptive role of Sub P under conditions of persistent inflammatory injury.

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Sex differences in the anatomical and functional organization of the periaqueductal gray‐rostral ventromedial medullary pathway in the rat: A potential circuit mediating the sexually dimorphic actions of morphine

Cited by 110 publications

References 119 publications

Morphine preferentially activates the periaqueductal gray–rostral ventromedial medullary pathway in the male rat: A potential mechanism for sex differences in antinociception

Morphine preferentially activates the periaqueductal gray–rostral ventromedial medullary pathway in the male rat: A potential mechanism for sex differences in antinociception

Nucleus paragigantocellularis afferents in male and female rats: Organization, gonadal steroid receptor expression, and activation during sexual behavior

Increased neuronal expression of neurokinin‐1 receptor and stimulus‐evoked internalization of the receptor in the rostral ventromedial medulla of the rat after peripheral inflammatory injury

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