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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Characterization of Specific Opioid Binding Sites in Neural Membranes from the Myenteric Plexus of Porcine Small Intestine

Department of Veterinary Pathobiology, College of Veterinary Medicine (D.T., D.R.B.), and Department of Medicinal Chemistry, College of Pharmacy (P.S.P.), University of Minnesota Academic Health Center, Minneapolis, Minnesota

- and -Opioid receptors (OPRs), but not µ-OPRs, are expressed in the myenteric plexus of the porcine distal small intestine. In a subpopulation of myenteric neurons, - and -OPRs seem to be colocalized and may functionally interact. In this study, radioligand binding was used to characterize myenteric OPR populations in detail. The nonselective OPR antagonist [³H]diprenorphine bound to a single, high-affinity site in myenteric neural membrane homogenates. Naloxone displaced 65 and 59% of [³H]diprenorphine binding from this site in Na⁺-free Tris and Krebs-HEPES buffers, respectively. Naltrexone-derived - and -OPR antagonists, including naltriben, 7-benzylidenenaltrexone, nor-binaltorphimine, and 5'-guanidinonaltrindole, displaced [³H]diprenorphine from two distinct binding sites to levels similar to that of naloxone. The selective -OPR ligands Tyr-1,2,3,4-tetrahydroisoquinoline-Phe-Phe-OH (TIPP), [D-Pen²,D-Pen⁵]enkephalin (DPDPE), [D-Ala², Glu⁴]deltorphin II, and (+)-4-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl)-N,N-diethylbenzamide (SNC-80) and the -OPR agonist (D-(5,7,8)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxoaspiro-(4,5)dec-8-yl) benzeneacetamide (U-69,593) displaced [³H]diprenorphine from three independent binding sites; these included high-affinity - and -OPR sites, and a residual binding site. Residual [³H]diprenorphine binding was displaced by the selective -OPR antagonist nor-binaltorphimine after saturation of and sites, respectively, with DPDPE and U-69,593. The residual binding site displayed low affinity for - and -OPR agonists and TIPP, as well as moderate affinity for naltrexone-derived ligands, properties reminiscent of -/-OPR heterodimers.

Address correspondence to: Dr. David R. Brown, Department of Veterinary Pathobiology, University of Minnesota, 1988 Fitch Ave., St. Paul, MN 55108-6010. E-mail: brown013{at}umn.edu

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