Sex differences in micro-opioid receptor expression in the rat midbrain periaqueductal gray are essential for eliciting sex differences in morphine analgesia - PubMed (original) (raw)
Sex differences in micro-opioid receptor expression in the rat midbrain periaqueductal gray are essential for eliciting sex differences in morphine analgesia
Dayna R Loyd et al. J Neurosci. 2008.
Abstract
Opioid-based narcotics are the most widely prescribed therapeutic agent for the alleviation of persistent pain; however, it is becoming increasingly clear that morphine is significantly less potent in women compared with men. Morphine primarily binds to mu-opioid receptors (MORs), and the periaqueductal gray (PAG) contains a dense population of MOR-expressing neurons. Via its descending projections to the rostral ventromedial medulla and the dorsal horn of the spinal cord, the PAG is considered an essential neural substrate for opioid-based analgesia. We hypothesized that MOR expression in the PAG was sexually dimorphic, and that these sex differences contribute to the observed sex differences in morphine potency. Using immunohistochemistry, we report that males had a significantly higher expression of MOR in the ventrolateral PAG compared with cycling females, whereas the lowest level of expression was observed in proestrus females. CFA-induced inflammatory pain produced thermal hyperalgesia in both males and females that was significantly reversed in males with a microinjection of morphine into the ventrolateral PAG; this effect was significantly greater than that observed in proestrus and estrus females. Selective lesions of MOR-expressing neurons in the ventrolateral PAG resulted in a significant reduction in the effects of systemic morphine in males only, and this reduction was positively correlated with the level of MOR expression in the ventrolateral PAG. Together, these results provide a mechanism for sex differences in morphine potency.
Figures
Figure 1.
A, B, Photomicrograph depicting μ-opioid receptor immunoreactivity in the caudal ventrolateral PAG (bregma −8.00) in a male (A) and a female (B) rat. Arrows denote MOR- immunoreactive cell bodies. C, Mean densitometry value of μ-opioid receptor immunoreactivity in male (closed bar) and proestrus, estrus, and diestrus females (open bars) averaged across the caudal PAG (bregma −7.04 to −8.30). *Significant effect.
Figure 2.
Photomicrograph of an intra-PAG injection site in the caudal ventrolateral PAG (bregma −8.00) of a representative male (A) and female (B) rat. aq, Aqueduct; vlPAG, ventrolateral periaqueductal gray; DR, dorsal raphe; scp, superior cerebellar pedunculus.
Figure 3.
A, Percent maximal possible effect of intra-PAG morphine administration of 5 and 10 μg in male (closed symbols) and 5, 10, and 18 μg in female (open symbols) rats. B, Percent maximal possible effect of intra-PAG morphine administration averaged across the time points 30, 60, and 90 min in male (closed bars) and female (open bars) rats. C, Percent maximal possible effect averaged over the 12, 15, and 18 μg/0.5 μl doses of intra-PAG morphine in proestrus, estrus, and diestrus females (open bars) compared with intact male (closed bars) rats. *Significant difference compared with males and diestrus females.
Figure 4.
A, Mean paw withdrawal latency in seconds to a thermal stimulus in proestrus, estrus, and diestrus female (open bars) compared with male (closed bars) rats. B, Mean paw withdrawal latency in seconds to a thermal stimulus after 24 h of CFA-induced inflammation in proestrus, estrus, and diestrus female (open bars) compared with male (closed bars) rats. C, Percent change in paw diameter after 24 h of CFA-induced inflammation.
Figure 5.
Illustration depicting localization of DermSAP (closed symbols) versus BlankSAP (open symbols) bilateral injection sites within the caudal ventrolateral PAG (bregma −7.04 to −8.30) of male (triangles) versus female (circles) rats.
Figure 6.
A, B, Photomicrograph depicting μ-opioid receptor density in the vlPAG (bregma −8.00) after BlankSAP (A) versus DermSAP (B) treatment. C, D, Photomicrograph depicting NeuN density in the vlPAG (bregma −8.00) after BlankSAP (C) versus DermSAP (D) treatment. E, F, Photomicrograph depicting tritiated DAMGO binding in the vlPAG (bregma −8.00) after BlankSAP (E) versus DermSAP (F) treatment.
Figure 7.
Paw withdrawal latencies to a thermal (A) or mechanical (B) painful stimulus before surgical manipulation (Pre-Lesion), after DermSAP or BlankSAP treatment (Pre-Inflamed), and after 24 h of CFA-induced hyperalgesia (Inflamed) in male (closed) versus female (open) rats.
Figure 8.
Percent maximal possible effect of cumulative doses of systemic morphine (0, 1.8, 3.2, 5.6, 8, 10, 18 mg/kg) in inflamed male (triangles) and female (circles) rats after DermSAP (closed symbols) or BlankSAP (open symbols).
Figure 9.
A, Densitometry value of MOR in the vlPAG of each individual male and female rat (open circle) after DermSAP or BlankSAP treatment within each group based on μ-opioid receptor density. B, C, Percent maximal possible effect of cumulative doses of systemic morphine (0, 1.8, 3.2, 5.6, 8, 10, 18 mg/kg) in inflamed male (B) and female (C) rats expressing low (1), moderate (2), and high (3) μ-opioid receptor density.
References
- Abols IA, Basbaum AI. Afferent connections of the rostral medulla of the cat: a neural substrate for midbrain-medullary interactions in the modulation of pain. J Comp Neurol. 1981;201:285–297. - PubMed
- Aubrun F, Marmion F. The elderly patient and postoperative pain treatment. Best Pract Res Clin Anaesthesiol. 2007;21:109–127. - PubMed
- Barrett AC, Cook CD, Terner JM, Craft RM, Picker MJ. Importance of sex and relative efficacy at the mu opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids. Psychopharmacology (Berl) 2001;158:154–164. - PubMed
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