Sex Differences in Analgesia: A Randomized Trial of μ versus κ Opioid Agonists

Miller, Penny; Ernst, Amy A.

doi:10.1097/01.smj.0000085743.68121.a9

Cited by 58 publications

(39 citation statements)

References 22 publications

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“…In studies using either acute (Kepler et al, 1989;Islam et al, 1993;Cicero et al, 1996;Cicero et al, 1997) or persistent pain models (Cook and Nickerson, 2005;Wang and Murphy, 2005), morphine has been shown to produce a significantly greater degree of analgesia in males in comparison to females. Similar findings have also been reported in humans (Cepeda and Carr, 2003;Miller and Ernst, 2004). The midbrain periaqueductal gray (PAG), along with its descending projections to the rostral ventromedial medulla (RVM), is one of the primary anatomical substrates mediating opioid analgesia.…”

Section: Introductionsupporting

confidence: 60%

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

Murphy

2006

J of Comparative Neurology

111

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Previous studies have demonstrated that morphine, administered systemically or directly into the PAG, produces a significantly greater degree of antinociception in males in comparison to females. As the midbrain periaqueductal gray (PAG) and its descending projections to the rostral ventromedial medulla (RVM) constitute an essential neural circuit for opioid-based analgesia, the present studies were conducted to determine if sex differences in the anatomical organization of the PAG-RVM pathway, and its activation during persistent inflammatory pain, could account for sex-based differences in opioid analgesia. In the rat, retrograde tracing was combined with Fos immunocytochemistry to investigate sexual dimorphism in the organization of the PAG-RVM circuit and its activation by persistent inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA). The ability of morphine to suppress the activation of the PAG-RVM circuit was also examined. Sexually dimorphic retrograde labeling was observed within the dorsomedial and lateral/ventrolateral PAG at all rostrocaudal levels, with females having significantly more PAG-RVM output neurons in comparison to males. While no sex differences were noted in the activation of the PAG-RVM circuit by persistent inflammatory pain, significantly more double labeled cells were found in males in comparison to females. Systemic administration of morphine significantly suppressed CFA-induced Fos in the PAG in males only. The results of these studies demonstrate that both the anatomical organization, and functional activation, of the PAG-RVM circuit is sexually dimorphic, and may provide the anatomical substrate for sex-based differences in morphine analgesia.

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Section: Introductionsupporting

confidence: 60%

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

Murphy

2006

J of Comparative Neurology

111

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“…This is in agreement with previous studies demonstrating marked sex differences in the potency and effectiveness of lower compared with higher efficacy opioid agonists using acute nociceptive pain tests (Cook et al, 2000;Barrett et al, 2002b). In contrast with preclinical findings in rats, in which butorphanol produces antinociception primarily through opioid receptors (Garner et al, 1997;Smith et al, 1999), in humans butorphanol as well as other mixed-action opioids exhibit analgesic profiles indicative of greater than opioid receptor involvement (Gear et al, 1996a,b;Miller and Ernst, 2004). This potential greater involvement of receptors with mixed-action opioids in humans may, in part, explain the findings that in humans females are more sensitive than males to the analgesic effects of butorphanol, nalbuphine, and pentazocine (Gear et al, 1996a(Gear et al, ,b, 1999.…”

Section: Discussioncontrasting

confidence: 43%

Nociceptive Sensitivity and Opioid Antinociception and Antihyperalgesia in Freund's Adjuvant-Induced Arthritic Male and Female Rats

Cook

Nickerson²

2004

J Pharmacol Exp Ther

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The present study was designed to examine sex differences in complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia and sex differences in opioid antinociception and antihyperalgesia. Female rats developed inflammation and hyperalgesia faster and exhibited greater peak hyperalgesia than male rats. In arthritic (CFA-treated) rats, lower thresholds were observed during estrus and proestrus, and in nonarthritic (vehicle-treated) rats, lower thresholds were observed during proestrus. Morphine and oxycodone were more potent in male than female arthritic rats, and butorphanol was more potent and effective in male than female arthritic rats. The potency of morphine was increased in arthritic rats, although to a greater magnitude in males. The potency of oxycodone was increased in male but not female arthritic rats. The potency of butorphanol was increased in arthritic male rats and the maximal antinociceptive effect of butorphanol was increased in arthritic female rats, but it did not result in greater than 20% antinociception. Morphine, oxycodone, and butorphanol all produced antihyperalgesic effects (returning thresholds of arthritic rats to the thresholds of nonarthritic rats) with greater potency in males than females. The peripherally acting opioid agonist loperamide produced intermediate levels of antinociception in male and female arthritic rats and no antinociception in nonarthritic rats. Loperamide was more potent in male than female arthritic rats at producing antihyperalgesia. These data demonstrate sex differences in arthritis-induced hyperalgesia and responsiveness to opioid analgesics. In arthritic rats, the antinociceptive effects of opioid agonists are most probably mediated by both central and peripheral opioid receptors, whereas their antihyperalgesic effects are mediated primarily by actions at peripheral opioid receptors.

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“…It may be too simplistic to expect one parameter to explain the differences observed. Nonetheless, it is important to understand the basis behind this sex difference, which may have important implications for pain management in women (Cepeda and Carr, 2003;Miller and Ernst, 2004).…”

Section: Discussionmentioning

confidence: 99%

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

160

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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Sex Differences in Analgesia: A Randomized Trial of μ versus κ Opioid Agonists

Abstract: Females had better pain scores with butorphanol than morphine at 60 minutes.

Cited by 58 publications

References 22 publications

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

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

Nociceptive Sensitivity and Opioid Antinociception and Antihyperalgesia in Freund's Adjuvant-Induced Arthritic Male and Female Rats

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

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