Importance of sex and relative efficacy at the µ opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids

Barrett, Andrew C.; Cook, Charles D.; Terner, Jolan M.; Craft, Rebecca M.; Picker, Mitchell J.

doi:10.1007/s002130100821

Cited by 74 publications

(63 citation statements)

References 24 publications

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“…Intact and GDX male and female F344 rats were obtained from Charles River Laboratories, Inc. (Wilmington, MA). Although sex differences have been observed in numerous rat strains, F344 rats were tested for the extremely robust and consistent sex differences observed in this strain in assays of phasic pain (Cook et al, 2000;Barrett et al, 2001). Gonadectomies were performed at the supplier when the rats were 3 months of age, and at least 3 weeks elapsed before any testing was conducted.…”

Section: Methodsmentioning

confidence: 99%

“…A second purpose was to compare the ability of the -opioids morphine, buprenorphine and dezocine to reverse this hyperalgesia in male and female rats. The use of the low-efficacy opioids buprenorphine and dezocine was of critical importance, since recent studies suggest that the magnitude of sex differences in opioid antinociception is considerably larger with less efficacious opioids (Barrett et al, 2001).…”

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confidence: 99%

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Capsaicin-Induced Hyperalgesia and μ-Opioid-Induced Antihyperalgesia in Male and Female Fischer 344 Rats

Barrett¹,

Smith²,

Picker³

2003

J Pharmacol Exp Ther

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The influence of sex in determining responses to opioid analgesics has been well established in rodents and monkeys in assays of short-lasting, phasic pain. The purpose of this investigation was to use a capsaicin model of tonic pain to evaluate sex differences in hyperalgesia and -opioid-induced antihyperalgesia in Fischer 344 (F344) rats. Capsaicin injected into the tail produced a dose-dependent thermal hyperalgesia in males and females, with the dose required to produce a comparable level of hyperalgesia being 3.0-fold higher in males than in females. These sex differences were modulated by gonadal hormones, inasmuch as gonadectomy increased the potency of capsaicin in males and decreased its potency in females. Morphine, buprenorphine, and dezocine administered by various routes [systemic (s.c.), local (in the tail), and central (i.c.v.)] generally produced marked antihyperalgesic effects in males and females. Although in most instances these opioids were equally potent and effective in males and females, selected doses of local and i.c.v. administered buprenorphine produced greater effects in females. When administered locally, the antihyperalgesic effects of morphine were mediated by peripheral opioid receptors in both males and females, since this effect was not reversed by i.c.v. naloxone methiodide. These data contrast with the finding that -opioids are more potent in male rodents in assays of phasic pain, thus suggesting that distinct mechanisms underlie male and female sensitivity to opioid antinociception in phasic and tonic pain models. These findings emphasize the need to test male and female rodents in tonic pain assays that may have greater relevance for human pain conditions.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Capsaicin-Induced Hyperalgesia and μ-Opioid-Induced Antihyperalgesia in Male and Female Fischer 344 Rats

Barrett¹,

Smith²,

Picker³

2003

J Pharmacol Exp Ther

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“…(Bodnar et al, 1988,Craft, 2003b,Craft, 2003a,Cook and Nickerson, 2005,Wang et al, 2006. Sex differences in morphine analgesia have been reported in studies employing orofacial (Okamoto et al, 2005), somatic (Bartok and Craft, 1997,Cicero et al, 1997,Boyer et al, 1998,Kest et al, 1999,Barrett et al, 2001) or visceral (Ji et al, 2006) pain models. To date, the mechanism(s) whereby morphine produces a differential degree of analgesia is unknown.…”

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confidence: 99%

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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“…Initial tests were conducted with morphine because it is the prototypical opioid receptor agonist that has been previously examined in male rats using the CFA model of chronic pain (Neil et al, 1986;Millan et al, 1987). The lower efficacy opioid butorphanol was also examined because the magnitude of opioid-induced sex differences in potency and effectiveness are greater with lower efficacy compared to higher efficacy opioid agonists (Cook et al, 2000;Barrett et al, 2001). Finally, tests with the higher efficacy agonist oxycodone, which is used in several formulations of commercially available opioid analgesics, including OxyContin, were conducted.…”

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confidence: 99%

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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Importance of sex and relative efficacy at the µ opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids

Cited by 74 publications

References 24 publications

Capsaicin-Induced Hyperalgesia and μ-Opioid-Induced Antihyperalgesia in Male and Female Fischer 344 Rats

Capsaicin-Induced Hyperalgesia and μ-Opioid-Induced Antihyperalgesia in Male and Female Fischer 344 Rats

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

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

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