Estrus Phase Differences in Female Rats in Morphine Antinociception Elicited From the Ventrolateral Periaqueductal Gray

Shane, Randi; Bernal, Sonia Y.; Rozengurtel, Shoshana; Bodnar, Richard J.

doi:10.1080/00207450600910259

Cited by 18 publications

(9 citation statements)

References 36 publications

(61 reference statements)

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“…Experiment 2 of the present study suggests that the same is true when morphine is administered directly into the vPAG. Bodnar and colleagues report similar findings [47]. Thus, it is likely that sex differences were not observed in Experiment 1 because only 7% of females were in estrus during testing.…”

Section: Discussionsupporting

confidence: 66%

PAG mu opioid receptor activation underlies sex differences in morphine antinociception

Bernal

Morgan

Craft

2007

Behavioural Brain Research

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Given the findings that (1) systemic opioid antinociception varies by estrous stage in females, and (2) the magnitude of sex differences in opioid antinociception is negatively correlated with opioid agonist efficacy, we hypothesized that sex differences in the function of the descending pain modulatory system are likely influenced by estrous stage in females and by the number of available opioid receptors therein. The present study tested these hypotheses by (1) comparing antinociception produced by morphine microinjection to the ventral periaqueductal gray (vPAG) in females at different stages of the estrous cycle, and (2) examining systemic morphine antinociception in males vs. females under conditions of reduced vPAG mu opioid receptor availability. When estrous stage of females was not controlled for (Experiment 1), there was no significant sex difference in tail withdrawal antinociception following morphine microinjection (0.3-10 μg), although morphine was more potent in males than females in producing immobility. Experiment 2 showed that intra-vPAG morphine produced less antinociception and immobility in estrus than in diestrus females; that is, only estrus females' response to morphine was lower than that of males. Experiment 3 showed that microinjection of the irreversible mu opioid antagonist β-funaltrexamine (β-FNA) into the vPAG shifted the systemic morphine dose-effect curve farther to the right in females than in males. That is, a reduction in available vPAG mu opioid receptors had a greater impact on opioid antinociception in females than in males, suggesting that females have fewer vPAG mu opioid receptors than males. Overall, these data suggest that ovarian hormones and PAG mu opioid receptor density contribute to sex differences in antinociception produced by morphine.

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Section: Discussionsupporting

confidence: 66%

PAG mu opioid receptor activation underlies sex differences in morphine antinociception

Bernal

Morgan

Craft

2007

Behavioural Brain Research

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“…Previous research has found that antinociceptive sex-differences to morphine microinjection into the vlPAG are dependent on the estrus cycle [3, 34]. Although estrus phase was not measured, sex-differences in antinociception were evident in the present study.…”

Section: Discussioncontrasting

confidence: 51%

Drug dependent sex-differences in periaqueducatal gray mediated antinociception in the rat

Bobeck

McNeal

Morgan

2009

Pain

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Mu-opioid receptor (MOPr) agonists, such as morphine, produce greater antinociception in male compared to female rats. The ventolateral periaqueductal gray (vlPAG) appears to contribute to this sex difference despite fewer vlPAG output neurons projecting to the rostral ventromedial medulla in male compared to female rats. This greater projection in female rats suggests that non-opioid activation of vlPAG output neurons should produce greater antinociception in female compared to male rats. This hypothesis was tested by comparing the time course and antinociceptive potency of microinjecting MOPr agonists (morphine, DAMGO, fentanyl) and non-opioid compounds (bicuculline, kainic acid) into the vlPAG of female and male rats. Microinjection of morphine or DAMGO produced antinociception that had a slow onset (peak from 15–30 min) and long duration (60 min) compared to the antinociception produced following microinjection of fentanyl, bicuculline, or kainic acid (peak effect at 3 min; duration less than 30 min). No sex-differences in the time courses were evident. All five compounds caused a dose-dependent antinociception when microinjected into the vlPAG. Antinociceptive potency was significantly greater in male compared to female rats following microinjection of morphine, DAMGO, and bicuculline, but not following microinjection of fentanyl or kainic acid. In no case did activation of the vlPAG produce greater antinocicepiton in female compared to male rats. These findings demonstrate that the vlPAG can produce comparable antinociception in female and male rats, but antinociception produced by inhibition of GABAergic neurons (whether by morphine or the GABAA receptor antagonist bicuculline) produces greater antinociception in males.

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“…However, estrogen's actions may not be generalizable and may depend upon GPCR type, route of drug administration and therefore the site of action (spinal versus supraspinal), genotype and source of the experimental animals. Indeed, supraspinal morphine (a muopioid receptor agonist) injection produced most potent antinociception in the proestrous phase (high estrogen) relative to the met-diestrus phases (low estrogen) in SD rats from Charles River Laboratories (Kepler et al, 1989;Shane et. al., 2007), whereas Bernal et al (2007) reported the most potent morphine antinociception in the diestrous phase relative to the estrous phase in SD rats from Taconic Farms.…”

Section: Discussionmentioning

confidence: 99%

Sex-specific modulation of spinal nociception by α2-adrenoceptors: Differential regulation by estrogen and testosterone

et al. 2008

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Sex-related differences in antinociception produced by the activation of α 2 -adrenoceptors (α 2 -ARs) have been reported, however, the precise role of gonadal steroids is still unknown. Hence, we hypothesized that estrogen and testosterone modulate antinociceptive effects of clonidine (an α 2 -AR agonist) on N-methyl-D-aspartate (NMDA)-and heat-induced spinal nociception. We also investigated whether estrogen-or testosterone alter the expression of α 2A -adrenoceptors in the spinal cord. Sprague-Dawley (SD) rats were implanted with PE10 cannulae in the intrathecal space of the lumbosacral spinal cord and divided into male, proestrous and diestrous female, ovariectomized (OVX), estradiol-treated OVX (OVX+E), castrated male (GDX), testosterone (GDX+T) and estrogen-treated GDX (GDX+E) groups. Clonidine dose-dependently inhibited NMDA-induced scratching behavior in the male and OVX groups but to a significantly lesser extent in the OVX+E group. It also increased the tail withdrawal latency in the male, OVX, diestrous and GDX+T groups but not in the OVX+E, proestrous, GDX and GDX+E groups. Levels of α 2A -AR mRNA were significantly higher in the OVX, estradiol-treated OVX, GDX and GDX+E animals. In contrast, α 2A -AR protein levels were higher in estradiol-treated OVX, GDX, GDX+T and GDX+E animals as compared to the male. Indeed, no correlations were observed between changes in the mRNA or protein levels of α 2A -AR and behavioral observations. These results support our hypothesis that sex-related differences in α 2 -AR-mediated modulation of spinal nociception are gonadal hormone-dependent: estrogen attenuates antinociceptive effects in females whereas testosterone is required for the expression of antinociception in males. In addition, results also revealed that the mechanism of action of gonadal hormones may not involve a global alternation in expression of α 2A -AR in the spinal cord. Estrogen-induced attenuation of α 2 -AR-mediated inhibition of nociception could contribute to the higher prevalence of pain syndromes in women. 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. Sex-related differences in the perception of pain and the response to analgesics have been reported with females having lower thresholds for pain (Notermans, 1966;Neri et al., 1984;Berkley, 1997;Riley et al., 1999;Rollman et al., 2000; reviewed in Keogh et al., 2002) and a larger number of pain sites as compared to males (Fillingim and Maixner, 1995;Berkley, 1997;Fillingim et al., 1999). In addition, many pain syndromes/disorders such as fibromyalgia, rheumatoid arthritis, irritable bowel syndr...

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Estrus Phase Differences in Female Rats in Morphine Antinociception Elicited From the Ventrolateral Periaqueductal Gray

Cited by 18 publications

References 36 publications

PAG mu opioid receptor activation underlies sex differences in morphine antinociception

PAG mu opioid receptor activation underlies sex differences in morphine antinociception

Drug dependent sex-differences in periaqueducatal gray mediated antinociception in the rat

Sex-specific modulation of spinal nociception by α2-adrenoceptors: Differential regulation by estrogen and testosterone

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