Pharmacogenetic analysis of sex differences in opioid antinociception in rats

Terner, Jolan M.; Lomas, Lisa M.; Smith, Eric; Barrett, Andrew C.; Picker, Mitchell J.

doi:10.1016/j.pain.2003.08.008

Cited by 78 publications

(58 citation statements)

References 30 publications

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“…This contrasts with reports (Cook et al, 2000;Terner et al, 2003) that a sex difference is more evident with lower efficacy -opioids. However, although Terner and colleagues also used the rat tail-withdrawal assay, they compared very low efficacy compounds, namely, buprenor- phine, butorphanol, and nalbuphine with morphine, and this may explain the discrepancy with the present findings.…”

Section: Discussioncontrasting

confidence: 88%

Comparison of the Antinociceptive Response to Morphine and Morphine-Like Compounds in Male and Female Sprague-Dawley Rats

Peckham

Traynor

2005

J Pharmacol Exp Ther

158

113

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Male rats are more sensitive to the antinociceptive effects of morphine than female rats. This difference is seen across several rat strains using a variety of nociceptive stimuli. However, the literature in regard to sex differences in antinociceptive responses to -opioids other than morphine is less consistent. The present study was designed to examine whether there is a structure-activity rationale that determines which -opioids will show a differential antinociceptive response between male and female rats. A series of morphinans closely related in structure to morphine, namely, codeine, heroin, hydrocodone, hydromorphone, oxymorphone, and oxycodone, were examined for their antinociceptive activity in male and female Sprague-Dawley rats and compared with the structurally unrelated -opioid agonists methadone and fentanyl. Antinociception was measured by the warm-water tail-withdrawal assay. The results show that morphine is more potent in males compared with females Ͼ hydromorphone ϭ hydrocodone ϭ oxymorphone, but there was no observable sex difference in the antinociceptive potency of codeine, heroin, oxycodone, methadone, or fentanyl. The potency to stimulate guanosine 5Ј-O-(3-[ 35 S]thio)triphosphate ([ 35 S]GTP␥S) binding and binding affinity of the various morphinans was compared in rat glioma C6 cells expressing the rat -opioid receptor; relative efficacy was also compared by stimulation of [35 S]GTP␥S binding in slices of rat brain thalamus. The presence of a sex difference in antinociceptive responsiveness was not related to drug potency, efficacy, or affinity. Consequently, it is likely that differential metabolism of the opioid, possibly by glucuronidation, determines the presence or absence of a sex difference.Male rats are more sensitive to the antinociceptive effects of morphine than female rats. These results seem to be consistent over several types of antinociceptive assays using a variety of nociceptive stimuli and behavioral endpoints.

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Section: Discussioncontrasting

confidence: 88%

Comparison of the Antinociceptive Response to Morphine and Morphine-Like Compounds in Male and Female Sprague-Dawley Rats

Peckham

Traynor

2005

J Pharmacol Exp Ther

158

113

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“…Previous studies comparing opioid agonists that vary in efficacy also support the hypothesis that differential opioid receptor density underlies sex differences in opioid antinociception. Picker and colleagues have demonstrated that sex differences in opioid antinociception increase in magnitude as the efficacy of the agonist decreases [4,11,52]. Because low to intermediate efficacy agonists must activate more receptors than high efficacy agonists to produce antinociception, the functional significance of small sex differences in opioid receptor density would be magnified when testing lower efficacy agonists.…”

Section: Discussionmentioning

confidence: 99%

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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“…The primary factor among these is genotype. Studies in mice 21,[30][31][32] and rats [32][33][34][35][36] have demonstrated that sex differences in pain and analgesia can be demonstrated in certain strains but not others. The effects of gonadal hormones on pain-related traits are similarly strain-dependent 21,37 .…”

Section: Male Onlymentioning

confidence: 99%

Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon

2012

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| A clear majority of patients with chronic pain are women; however, it has been surprisingly difficult to determine whether this sex bias corresponds to actual sex differences in pain sensitivity. A survey of the currently available epidemiological and laboratory data indicates that the evidence for clinical and experimental sex differences in pain is overwhelming. Various explanations for this phenomenon have been given, ranging from experiential and sociocultural differences in pain experience between men and women to hormonally and genetically driven sex differences in brain neurochemistry. PERSPECTIVES NATURE REVIEWS | NEUROSCIENCE VOLUME 13 | DECEMBER 2012 | 859

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Pharmacogenetic analysis of sex differences in opioid antinociception in rats

Cited by 78 publications

References 30 publications

Comparison of the Antinociceptive Response to Morphine and Morphine-Like Compounds in Male and Female Sprague-Dawley Rats

Comparison of the Antinociceptive Response to Morphine and Morphine-Like Compounds in Male and Female Sprague-Dawley Rats

PAG mu opioid receptor activation underlies sex differences in morphine antinociception

Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon

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