title: Effects of intrathecal SNC80, a delta receptor ligand, on nociceptive threshold and dorsal horn substance p release.
abstract: Delta-opioid receptors (DOR) are present in the superficial dorsal horn and are believed to regulate the release of small afferent transmitters as evidenced by the effects of spinally delivered delta-opioid preferring peptides. Here we examined the effects of intrathecal SNC80 [(+)-4-[α(R)-α-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-(methoxybenzyl)-N,N-diethylbenzamide], a selective nonpeptidic DOR agonist, in three preclinical pain models, acute thermal escape, intraplantar carrageenan-tactile allodynia, and intraplantar formalin flinches, and on the evoked release of substance P (SP) from small primary afferents. Rats with chronic intrathecal catheters received intrathecal vehicle or SNC80 (100 or 200 μg). Intrathecal SNC80 did not change acute thermal latencies or carrageenan-induced thermal hyperalgesia. However, SNC80 attenuated carrageenan-induced tactile allodynia and significantly reduced both phase 1 and phase 2 formalin-induced paw flinches, as assessed by an automatic flinch counting device. These effects were abolished by naltrindole (3 mg/kg i.p.), a selective DOR antagonist, but not CTOP (10 µg i.t.), a selective MOR antagonist. Furthermore, intrathecal SNC80 (200 μg) blocked formalin-induced substance P release otherwise evoked in the ispilateral superficial dorsal horn as measured by NK1 receptor internalization. In conclusion, intrathecal SNC80 alleviated pain hypersensitivity after peripheral inflammation in a fashion paralleling its ability to block peptide transmitter release from small peptidergic afferents, which by its pharmacology appears to represent an effect mediated by a spinal DOR.
authors: Department of Anesthesiology, University of California San Diego, La Jolla, California (M.K., T.L.Y., Q.X.); Department of Pharmacology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (M.K.); and Department of Anesthesiology, Dokkyo Medical University, School of Medicine, Mibu, Tochigi Prefecture, Japan (T.Ta., T.Te.).
authors: Milad
authors: M
authors: Kouchek
authors: Toshifumi
authors: T
authors: Takasusuki
authors: Tetsuji
authors: T
authors: Terashima
authors: Tony L
authors: TL
authors: Yaksh
authors: Qinghao
authors: Q
authors: Xu
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D007278:Injections, Spinal; D008024:Ligands; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors; D013373:Substance P / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D001549:Benzamides; D008024:Ligands; D010879:Piperazines; D018040:Receptors, Neurokinin-1; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D013373:Substance P
references: J Med Chem. 1994 Jul 8;37(14):2125-8
references: 8035418
references: Nature. 1975 Dec 18;258(5536):577-80
references: 1207728
references: Mol Pain. 2010 Oct 26;6:71
references: 20977770
references: Annu Rev Pharmacol Toxicol. 2000;40:389-430
references: 10836142
references: J Comp Neurol. 2009 Apr 1;513(4):385-98
references: 19180644
references: J Pharmacol Exp Ther. 2005 Sep;314(3):1362-9
references: 15908510
references: Lancet. 1983 Jun 18;1(8338):1386-7
references: 6134164
references: J Neurosci. 2004 Mar 17;24(11):2806-12
references: 15028774
references: J Pharmacol Exp Ther. 1995 Apr;273(1):359-66
references: 7714789
references: J Neurosci. 2011 Sep 14;31(37):13068-77
references: 21917790
references: Pain. 1986 Feb;24(2):205-209
references: 3008062
references: Physiol Behav. 1976 Dec;17(6):1031-6
references: 14677603
references: Eur J Pharmacol. 1995 Apr 13;277(1):21-8
references: 7635169
references: Methods Mol Med. 2004;99:109-21
references: 15131333
references: Cell. 2009 Jun 12;137(6):1148-59
references: 19524516
references: J Pharmacol Exp Ther. 1993 Aug;266(2):577-84
references: 8394911
references: Neuroscience. 1977;2(4):593-6
references: 917285
references: Brain Res. 2002 Mar 15;930(1-2):150-62
references: 11879805
references: J Neurosci Methods. 1994 Jul;53(1):55-63
references: 7990513
references: J Clin Psychiatry. 2002;63 Suppl 11:6-10
references: 12562137
references: Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13117-22
references: 20615975
references: Nature. 2012 May 16;485(7398):400-4
references: 22596164
references: J Pharmacol Exp Ther. 1995 Dec;275(3):1535-42
references: 8531126
references: Eur J Pharmacol. 1993 May 12;236(1):89-96
references: 8391455
references: J Comp Neurol. 2001 Jan 22;429(4):590-600
references: 11135237
references: J Pharmacol Exp Ther. 1991 Nov;259(2):725-31
references: 1658309
references: Biochem Biophys Res Commun. 1995 Mar 8;208(1):302-8
references: 7887943
references: J Pharmacol Exp Ther. 1998 Jul;286(1):362-75
references: 9655881
references: J Neurosci. 2005 Apr 6;25(14):3551-9
references: 15814785
references: Pharmacol Rev. 1987 Sep;39(3):197-249
references: 2827196
references: J Neurosci. 1995 Sep;15(9):5976-88
references: 7666182
references: J Pharmacol Exp Ther. 1983 Aug;226(2):303-16
references: 6308205
references: Brain Res. 1982 Sep 9;247(1):75-83
references: 6127147
references: Brain Res. 1978 Jun 16;148(2):516-20
references: 207391
references: Neuroscience. 2003;118(2):535-45
references: 12699788
references: J Appl Physiol (1985). 2001 Jun;90(6):2386-402
references: 11356806
references: J Physiol. 1998 Dec 15;513 ( Pt 3):787-804
references: 9824718
references: J Pharmacol Exp Ther. 2000 Dec;295(3):1135-41
references: 11082450
references: J Pharmacol Exp Ther. 1998 Jan;284(1):378-87
references: 9435201
references: Neuroscience. 2010 Nov 24;171(1):344-50
references: 20736053
references: Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2622-6
references: 7535928
references: J Neurosci. 1999 Oct 1;19(19):8337-48
references: 10493735
references: J Comp Neurol. 2003 Oct 20;465(3):349-60
references: 12966560
references: J Neurosci Methods. 1997 Oct 3;76(2):183-91
references: 9350970
references: Anesthesiology. 2007 Nov;107(5):807-12
references: 18073556
references: Neuroscience. 2008 Mar 3;152(1):119-27
references: 18222611
references: Proc Natl Acad Sci U S A. 1987 Aug;84(15):5487-91
references: 2440052
references: Pharmacol Biochem Behav. 2009 Feb;91(4):566-72
references: 18929596
references: Peptides. 1989 Nov-Dec;10(6):1127-31
references: 2482963
references: J Neurosci. 1997 Oct 15;17(20):8049-60
references: 9315923
references: Pain. 1985 Nov;23(3):213-221
references: 3906516
references: Anesthesiology. 2011 Jul;115(1):153-64
references: 21577088
references: J Pharmacol Exp Ther. 1992 Oct;263(1):264-75
references: 1328610
references: J Neurosci. 2009 Oct 21;29(42):13264-73
references: 19846714
references: J Pharmacol Exp Ther. 1995 Oct;275(1):63-72
references: 7562596
references: J Neurosci. 1994 Aug;14(8):4882-90
references: 8046458
references: Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13525-30
references: 17686976
references: Eur J Neurosci. 2008 May;27(10):2558-67
references: 18513322
references: J Neurosci. 2005 Apr 6;25(14):3651-60
references: 15814796