Opioid modulation of ferret vagal afferent mechanosensitivity.
Despite universal use of opioids in the clinic to inhibit pain, there is relatively little known of their peripheral actions on sensory nerve endings, where in fact they may be better targeted with more widespread applications. Here we show differential effects of mu-, kappa-, and delta-opioids on mechanosensitive ferret esophageal vagal afferent endings investigated in vitro. The effects of selective agonists [d-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (DAMGO), 2-(3, 4-dichlorophenyl)-N-methyl-N-[(1S)-1phenyl-2-(1-pyrrolidinyl) ethyl] acetamide hydrochlorine (ICI 199441), and (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80), respectively, on mechanosensory stimulus-response functions were quantified. DAMGO (10(-7) to 10(-5) M) reduced the responses of tension receptors to circumferential tension (1-5 g) by up to 50%, and the responses of mucosal receptors to mucosal stroking (10-1,000 mg von Frey hair) by >50%. DAMGO effects were reversed by naloxone (10(-5) M). Tension/mucosal (TM) receptor responses to tension and stroking were unaffected by DAMGO. ICI 199441 (10(-6) to 10(-5) M) potently inhibited all responses except TM receptor responses to tension, and SNC-80 (10(-5) to 10(-3) M) had no effect other than a minor inhibition of mucosal receptor responses to intense stimuli at 10(-3) M. We conclude that mu- and kappa-opioids have potent and selective peripheral effects on esophageal vagal afferents that may have applications in treatment of disorders of visceral sensation.
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Amanda J
AJ
Nerve Gut Research Laboratory, Department of Gastroenterology and Hepatology, Level 1 Hanson Institute, Royal Adelaide Hospital, Frome Rd., Adelaide, SA 5000, Australia. amanda.page@health.sa.gov.au
O'Donnell
Tracey A
TA
Blackshaw
L Ashley
LA
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004947:Esophagus / Q000294:innervation*; D005289:Ferrets; D040542:Mechanotransduction, Cellular / Q000187:drug effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D010812:Physical Stimulation; D010879:Piperazines / Q000494:pharmacology; D011312:Pressure; D011759:Pyrrolidines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013270:Stomach / Q000294:innervation*; D014630:Vagus Nerve / Q000187:drug effects* / Q000378:metabolism
D000701:Analgesics, Opioid; D001549:Benzamides; D009292:Narcotic Antagonists; D010879:Piperazines; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C058468:ICI 199441; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D009270:Naloxone