title: Functional selectivity of kappa opioid receptor agonists in peripheral sensory neurons.
abstract: Activation of kappa opioid receptors (KORs) expressed by peripheral sensory neurons that respond to noxious stimuli (nociceptors) can reduce neurotransmission of pain stimuli from the periphery to the central nervous system. We have previously shown that the antinociception dose-response curve for peripherally restricted doses of the KOR agonist (-)-(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50488) has an inverted U shape. Here, we found that the downward phase of the U50488 dose-response curve was blocked by an inhibitor of extracellular signal-regulated kinase (ERK) activation U0126. Local administration of the selective KOR agonist salvinorin A (Sal-A), also resulted in an inverted U-shaped curve; however, the downward phase was insensitive to U0126. By contrast, inhibition of c-Jun N-terminal kinase (JNK) partially blocked the downward phase of the dose-response curve to Sal-A, suggesting a role for JNK. In cultures of peripheral sensory neurons, U50488 and Sal-A inhibited adenylyl cyclase activity with similar efficacies; however, their ability to activate ERK and JNK differed. Whereas U50488 activated ERK but not JNK, Sal-A activated JNK but not ERK. Moreover, although both U50488 and Sal-A produced homologous desensitization, desensitization to U50488 was blocked by inhibition of ERK activation, whereas desensitization to Sal-A was blocked by inhibition of JNK. Substitution of an ethoxymethyl ether for the C2 position acetyl group of Sal-A reduced stimulation of JNK, prevented desensitization by ethoxymethyl ether for the C2 position acetyl group of Sal-A, and resulted in a monotonic antinociception dose-response curve. Collectively, these data demonstrate the functional selectivity of KOR ligands for signaling in peripheral sensory neurons, which results in differential effects on behavioral responses in vivo.
authors: Department of Pharmacology (R.J.J., B.A.J., L.C.S., T.A.C., W.P.C., K.A.B.), University of Texas Health Science Center, San Antonio, Texas; and Department of Medicinal Chemistry (R.M.S., T.E.P.), University of Kansas School of Pharmacy, Lawrence, Kansas.
authors: Raehannah J
authors: RJ
authors: Jamshidi
authors: Department of Pharmacology (R.J.J., B.A.J., L.C.S., T.A.C., W.P.C., K.A.B.), University of Texas Health Science Center, San Antonio, Texas; and Department of Medicinal Chemistry (R.M.S., T.E.P.), University of Kansas School of Pharmacy, Lawrence, Kansas.
authors: Blaine A
authors: BA
authors: Jacobs
authors: Department of Pharmacology (R.J.J., B.A.J., L.C.S., T.A.C., W.P.C., K.A.B.), University of Texas Health Science Center, San Antonio, Texas; and Department of Medicinal Chemistry (R.M.S., T.E.P.), University of Kansas School of Pharmacy, Lawrence, Kansas.
authors: Laura C
authors: LC
authors: Sullivan
authors: Department of Pharmacology (R.J.J., B.A.J., L.C.S., T.A.C., W.P.C., K.A.B.), University of Texas Health Science Center, San Antonio, Texas; and Department of Medicinal Chemistry (R.M.S., T.E.P.), University of Kansas School of Pharmacy, Lawrence, Kansas.
authors: Teresa A
authors: TA
authors: Chavera
authors: Department of Pharmacology (R.J.J., B.A.J., L.C.S., T.A.C., W.P.C., K.A.B.), University of Texas Health Science Center, San Antonio, Texas; and Department of Medicinal Chemistry (R.M.S., T.E.P.), University of Kansas School of Pharmacy, Lawrence, Kansas.
authors: Rachel M
authors: RM
authors: Saylor
authors: Department of Pharmacology (R.J.J., B.A.J., L.C.S., T.A.C., W.P.C., K.A.B.), University of Texas Health Science Center, San Antonio, Texas; and Department of Medicinal Chemistry (R.M.S., T.E.P.), University of Kansas School of Pharmacy, Lawrence, Kansas.
authors: Thomas E
authors: TE
authors: Prisinzano
authors: Department of Pharmacology (R.J.J., B.A.J., L.C.S., T.A.C., W.P.C., K.A.B.), University of Texas Health Science Center, San Antonio, Texas; and Department of Medicinal Chemistry (R.M.S., T.E.P.), University of Kansas School of Pharmacy, Lawrence, Kansas.
authors: William P
authors: WP
authors: Clarke
authors: Department of Pharmacology (R.J.J., B.A.J., L.C.S., T.A.C., W.P.C., K.A.B.), University of Texas Health Science Center, San Antonio, Texas; and Department of Medicinal Chemistry (R.M.S., T.E.P.), University of Kansas School of Pharmacy, Lawrence, Kansas berg@uthscsa.edu.
authors: Kelly A
authors: KA
authors: Berg
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D061251:Primary Cell Culture; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D012668:Trigeminal Ganglion / Q000166:cytology*
chemical_list: D002070:Butadienes; D045785:Diterpenes, Clerodane; D009570:Nitriles; D017473:Receptors, Opioid, kappa; C113580:U 0126; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000242:Cyclic AMP; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015232:Dinoprostone; C090499:salvinorin A