title: Opioid receptor characterisation of neuronally stimulated isolated human vas deferens.
abstract: Rodent vas deferens is routinely used as a native tissue preparation to assess opioid pharmacology of new compounds. The aim of this study was to investigate the effects of a selected number of opioid compounds in the human vas deferens. Stable contractions to electrical field stimulation (EFS) were inhibited by guanethidine (1 μM) and tetrodotoxin (TTX, 1 μΜ), confirming neuronally induced contractions. Contractile responses to EFS were inhibited by the selective δ-opioid agonists (DPDPE ([D-Pen2,5]enkephalin), PF-391459 (3-{4-[(R)-[(2S,5R)-4-benzyl-2,5-dimethylpiperazin-1-yl](3-hydroxyphenyl)methyl]phenyl}propanoic acid) and SNC-80 ((+)-4-[(αR)-α-((2 S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide)) (tested from 1 ρM to 10 μM or maximum), and the μ-opioid agonists DAMGO ([D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin), loperamide and SC-50484 (N-{2-[(N-acetyl-L-phenylalanyl)amino]-1,1-dimethylethyl}-L-tyrosinamide). There was no effect using the selective κ agonist U50488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide) (tested from 1 ρM to 10 μM). The selective δ-opioid antagonist naltrindole (10 nM) surmountably antagonised the responses to DPDPE, but not to PF-3911459. Responses to DAMGO were completely abolished in the presence of the μ-opioid antagonist CTAP (3 μM), which only weakly antagonised responses to SC-50484. We conclude that under these conditions, δ and μ-opioid receptors, but not κ-opioid receptors, are functional in the neuronally stimulated longitudinal human vas deferens. Additionally, the human vas deferens preparation can be used as part of a drug discovery screening project to assess opioid potency, efficacy and selectivity at native human tissues, thus providing more confidence in translation.
authors: Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK. rootjames473@gmail.com
authors: James
authors: J
authors: Root
authors: Ana Monica Lopes Correia
authors: AM
authors: Wakenhut
authors: Holly
authors: H
authors: Siggins
authors: Sidath
authors: S
authors: Katugampola
authors: Carolyn
authors: C
authors: Napier
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000494:pharmacology; D004558:Electric Stimulation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction; D009292:Narcotic Antagonists / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu