Abstract
We examined whether sex differences in κ-opioid receptor (KOPR) pharmacology exist in guinea pigs, which are more similar to humans in the expression level and distribution of KOPR in the brain than rats and mice. The KOPR agonist trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)benzeneacetamide methanesulfonate (U50,488H) produced a dose-dependent increase in abnormal postures and immobility with more effects in males than females. Males also showed more U50,488H-induced antinociception in the paw pressure test than females. Pretreatment with the KOPR antagonist norbinaltorphimine blocked U50,488H-induced abnormal body postures and antinociception. In contrast, inhibition of cocaine-induced hyperambulation by U50,488H was more effective in females than males. Thus, sex differences in the effects of U50,488H are endpoint-dependent. We then examined whether sex differences in KOPR levels and KOPR-mediated G protein activation in brain regions may contribute to the observed differences using quantitative in vitro autoradiography of [3H](5a,7a,8b)-(−)-N-methyl-N-(7-(1-pyrrolidinyl)1-oxaspiro(4,5)dec-8-yl)benzeacetamide ([3H]U69,593) binding to the KOPR and U50,488H-stimulated guanosine 5′-O-(3-[35S]thiotriphosphate ([35S]GTPγS) binding. Compared with females, males exhibited more [3H]U69,593 binding in the deep layers of somatosensory and insular cortices, claustrum, endopiriform nucleus, periaqueductal gray, and substantial nigra. Concomitantly, U50,488H-stimulated [35S]GTPγS binding was greater in males than females in the superficial and deep layers of somatosensory and insular cortices, caudate putamen, claustrum, medial geniculate nucleus, and cerebellum. In contrast, compared with males, females showed more U50,488H-stimulated [35S]GTPγS binding in the dentate gyrus and a trend of higher [35S]GTPγS binding in the hypothalamus. These data demonstrate that males and females differ in KOPR expression and KOPR-mediated G protein activation in distinct brain regions, which may contribute to the observed sex differences in KOPR-mediated pharmacology.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA17302, P30-DA13429 (to L.-Y.L.-C.), T32-DA07237 (to K.R.)] and by the Pennsylvania Department of Health.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.183905.
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ABBREVIATIONS:
- KOPR
- κ-opioid receptor
- ANOVA
- analysis of variance
- AUC
- area under the curve
- MOPR
- μ-opioid receptor
- norBNI
- norbinaltorphimine dihydrochloride
- PAG
- periaqueductal gray
- U50,488H (U50)
- trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)benzeneacetamide methanesulfonate
- U69,593
- (5a,7a,8b)-(−)-N-methyl-N-(7-(1-pyrrolidinyl)1-oxaspiro(4,5)dec-8-yl)benzeacetamide
- [35S]GTPγS
- guanosine 5′-O-(3-[35S]thiotriphosphate
- DA
- dopamine
- DAT
- DA transporter
- G/R
- [35S]GTPγS binding/[3H]U69,593 binding.
- Received May 12, 2011.
- Accepted August 11, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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