title: Teleantagonism: A pharmacodynamic property of the primary nociceptive neuron.
abstract: Previous work from our group showed that intrathecal (i.t.) administration of substances such as glutamate, NMDA, or PGE(2) induced sensitization of the primary nociceptive neuron (PNN hypernociception) that was inhibited by a distal intraplantar (i.pl.) injection of either morphine or dipyrone. This pharmacodynamic phenomenon is referred to in the present work as "teleantagonism". We previously observed that the antinociceptive effect of i.t. morphine could be blocked by injecting inhibitors of the NO signaling pathway in the paw (i.pl.), and this effect was used to explain the mechanism of opioid-induced peripheral analgesia by i.t. administration. The objective of the present investigation was to determine whether this teleantagonism phenomenon was specific to this biochemical pathway (NO) or was a general property of the PNNs. Teleantagonism was investigated by administering test substances to the two ends of the PNN (i.e., to distal and proximal terminals; i.pl. plus i.t. or i.t. plus i.pl. injections). We found teleantagonism when: (i) inhibitors of the NO signaling pathway were injected distally during the antinociception induced by opioid agonists; (ii) a nonselective COX inhibitor was tested against PNN sensitization by IL-1beta; (iii) selective opioid-receptor antagonists tested against antinociception induced by corresponding selective agonists. Although the dorsal root ganglion seems to be an important site for drug interactions, the teleantagonism phenomenon suggests that, in PNNs, a local sensitization spreads to the entire cell and constitutes an intriguing and not yet completely understood pharmacodynamic property of this group of neurons.
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049-900, São Paulo, Brazil.
authors.forename: Mani I
authors.initials: MI
authors.lastname: Funez
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Ferrari
authors.forename: Djane B
authors.initials: DB
authors.lastname: Duarte
authors.forename: Daniela
authors.initials: D
authors.lastname: Sachs
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Lorenzetti
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Parada
authors.forename: Sérgio H
authors.initials: SH
authors.lastname: Ferreira
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects*; D010069:Oxadiazoles / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D009292:Narcotic Antagonists; D010069:Oxadiazoles; D011759:Pyrrolidines; D011810:Quinoxalines; C060223:ICI 204448; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D009270:Naloxone; D009020:Morphine; D015232:Dinoprostone; D004298:Dopamine; D007213:Indomethacin
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15792-7
references.pmid: 9861049
references.citation: Neuropharmacology. 1994 Nov;33(11):1479-85
references.pmid: 7532832
references.citation: Physiol Behav. 1976 Dec;17(6):1031-6
references.pmid: 14677603
references.citation: J Comp Neurol. 1991 Apr 15;306(3):382-92
references.pmid: 1864999
references.citation: Pain. 2007 Jul;130(1-2):14-24
references.pmid: 17196338
references.citation: Inflamm Res. 1996 Oct;45(10):499-502
references.pmid: 8912014
references.citation: Nature. 1980 Nov 27;288(5789):373-6
references.pmid: 6253831
references.citation: J Pharmacol Exp Ther. 1987 Oct;243(1):258-63
references.pmid: 2822900
references.citation: Trends Pharmacol Sci. 2001 Jan;22(1):27-31
references.pmid: 11165669
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2923-8
references.pmid: 12589028
references.citation: N Engl J Med. 1991 Oct 17;325(16):1123-6
references.pmid: 1653901
references.citation: Eur J Pharmacol. 1987 Mar 17;135(2):145-53
references.pmid: 2884117
references.citation: Nature. 1988 Aug 25;334(6184):698-700
references.pmid: 3137474
references.citation: Br J Pharmacol. 1988 Jan;93(1):85-92
references.pmid: 3349235
references.citation: Eur J Pharmacol. 1984 Mar 16;99(1):23-9
references.pmid: 6723790
references.citation: Pharmacol Ther. 2006 Oct;112(1):116-38
references.pmid: 16730375
references.citation: J Neurosci. 1998 Dec 15;18(24):10345-55
references.pmid: 9852572
references.citation: J Pharmacol Exp Ther. 1988 Jan;244(1):181-9
references.pmid: 2826766
references.citation: Neurosci Lett. 1992 Dec 7;147(2):217-20
references.pmid: 1283459
references.citation: Br J Pharmacol. 1989 Apr;96(4):986-92
references.pmid: 2568146
references.citation: Eur J Pharmacol. 1978 Dec 15;53(1):39-48
references.pmid: 310771
references.citation: J Biol Chem. 1999 May 28;274(22):15719-24
references.pmid: 10336471
references.citation: J Neurosci. 1999 Mar 15;19(6):2181-6
references.pmid: 10066271
references.citation: Prog Neurobiol. 2001 Jul;64(4):327-63
references.pmid: 11275357
references.citation: Pain. 1983 Jun;16(2):109-110
references.pmid: 6877845
references.citation: Neuroscience. 1991;44(1):131-5
references.pmid: 1722888
references.citation: J Physiol. 1999 Apr 1;516 ( Pt 1):163-78
references.pmid: 10066931
references.citation: J Neurosci Methods. 2007 Jan 30;159(2):236-43
references.pmid: 16973217
references.citation: Nature. 1988 Jun 16;333(6174):664-6
references.pmid: 3131684
references.citation: Neurosci Lett. 1998 Jul 24;251(2):121-4
references.pmid: 9718989
references.citation: Prostaglandins. 1979 Aug;18(2):179-90
references.pmid: 230542
references.citation: Nature. 1974 Mar 1;248(5443):24-7
references.pmid: 4361995
references.citation: Pharmacol Rev. 1991 Jun;43(2):109-42
references.pmid: 1852778
references.citation: Prostaglandins. 1979 Aug;18(2):191-200
references.pmid: 230543
references.citation: J Neurophysiol. 1997 Jan;77(1):167-76
references.pmid: 9120557
references.citation: J Pharmacol Toxicol Methods. 1994 Dec;32(4):197-200
references.pmid: 7881133
references.citation: Neurosci Biobehav Rev. 2006;30(2):203-14
references.pmid: 16157378
references.citation: Agents Actions Suppl. 1991;32:101-6
references.pmid: 1676874
references.citation: Prostaglandins. 1979 Aug;18(2):201-8
references.pmid: 523678
references.citation: Br J Pharmacol. 1999 Jun;127(3):671-8
references.pmid: 10401557
references.citation: J Neurosci. 2006 Jan 18;26(3):953-62
references.pmid: 16421315