Abstract
The peripheral δ opioid receptor (DOR) is an attractive target for analgesic drug development. There is evidence that DOR can form heteromers with the κ-opioid receptor (KOR). As drug targets, heteromeric receptors offer an additional level of selectivity and, because of allosteric interactions between protomers, functionality. Here we report that selective KOR antagonists differentially altered the potency and/or efficacy of DOR agonists in primary cultures of adult rat peripheral sensory neurons and in a rat behavioral model of thermal allodynia. In vitro, the KOR antagonist nor-binaltorphimine (nor-BNI) enhanced the potency of [d-Pen2,5]-enkephalin (DPDPE), decreased the potency of [d-Ala2,d-Leu5]-enkephalin (DADLE), and decreased the potency and efficacy of 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC80) to inhibit prostaglandin E2 (PGE2)-stimulated adenylyl cyclase activity. In vivo, nor-BNI enhanced the effect of DPDPE and decreased the effect of SNC80 to inhibit PGE2-stimulated thermal allodynia. In contrast to nor-BNI, the KOR antagonist 5′-guanidinonaltrindole (5′-GNTI) reduced the response of DPDPE both in cultured neurons and in vivo. Evidence for DOR-KOR heteromers in peripheral sensory neurons included coimmunoprecipitation of DOR with KOR, a DOR-KOR heteromer selective antibody augmented the antinociceptive effect of DPDPE in vivo, and the DOR-KOR heteromer agonist 6′-GNTI inhibited adenylyl cyclase activity in vitro as well as PGE2-stimulated thermal allodynia in vivo. Taken together, these data suggest that DOR-KOR heteromers exist in rat primary sensory neurons and that KOR antagonists can act as modulators of DOR agonist responses most likely through allosteric interactions between the protomers of the DOR-KOR heteromer.
Footnotes
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA024865] (to W.P.C.), [Grant DA026619] (to K.A.B.), [Grant DA008863] (to L.A.D.); and [Grant DA01533] (to P.S.P.); and the National Institutes of Health National Institute of Dental and Craniofacial Research [Grant DE14318] (to M.P.R., B.A.M.).
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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ABBREVIATIONS:
- BK
- bradykinin
- DPDPE
- [d-Pen2,5]-enkephalin
- PGE2
- prostaglandin E2
- TG
- trigeminal ganglion
- DADLE
- [d-Ala2,d-Leu5]-enkephalin
- MOR
- μ opioid receptor
- KOR
- κ opioid receptor
- DOR
- δ-opioid receptor
- 6′-GNTI
- 6′-guanidinonaltrindole
- nor-BNI
- nor-binaltorphimine
- CB
- cannabinoid
- HEK
- human embryonic kidney
- PVDF
- polyvinyl difluoride
- BK
- bradykinin
- PWL
- paw withdrawal latency
- NTI
- naltrindole
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
- AT1
- angiotensin II type 1.
- Received April 4, 2011.
- Accepted November 9, 2011.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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