title: Evidence for a novel, neurohumoral antinociceptive mechanism mediated by peripheral capsaicin-sensitive nociceptors in conscious rats.
abstract: Stimulation of capsaicin-sensitive peripheral sensory nerve terminals induces remote anti-inflammatory effects throughout the body of anesthetized rats and guinea-pigs mediated by somatostatin. As somatostatin has also antinociceptive effects, the study aimed at investigating whether similar remote antinociceptive effects can be demonstrated in awake animals. In conscious rats, nociceptive nerve endings of the right hind paw decentralized by cutting the sciatic and saphenous nerves 18h before were chemically stimulated, and drop of the noxious heat threshold (heat hyperalgesia) induced by prior (18h before) plantar incision was measured on the contralateral, left hind paw using an increasing-temperature water bath. 18h after nerve transection, mustard oil-evoked plasma extravasation was not significantly reduced in the right hind paw as tested by in vivo fluorescence imaging. Applying agonist of either transient receptor potential vanilloid 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1) receptor (capsaicin or mustard oil, respectively) to the nerve-transected paw inhibited the plantar incision-induced drop of the noxious heat threshold on the contralateral paw. The onset of these remote antihyperalgesic effects was 10-20min. A similar contralateral inhibitory effect of capsaicin or mustard oil treatment was observed on neuropathic mechanical hyperalgesia evoked by partial sciatic nerve injury 2days before nerve transection and measured by a Randall-Selitto apparatus. The remote thermal antihyperalgesic effect was prevented by chronic (5days) denervation or local capsaicin desensitization of the stimulated paw; reduced by intraperitoneally applied antagonist of somatostatin (cyclosomatostatin) or opioid receptors (naloxone). The response was mimicked by intraperitoneally applied somatostatin and associated with a 72±27% increase in plasma somatostatin-like immunoreactivity that was absent after chronic (5days) denervation. In conclusion, chemical activation of decentralized peripheral capsaicin-sensitive nociceptors evokes remote antihyperalgesic responses initiated outside the central nervous system and mediated by somatostatin and endogenous opioids.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary. Electronic address: gabor.petho@aok.pte.hu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Pethő
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary; Molecular Pharmacology Research Team, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary.
authors.forename: Kata
authors.initials: K
authors.lastname: Bölcskei
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary.
authors.forename: Réka
authors.initials: R
authors.lastname: Füredi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary; Molecular Pharmacology Research Team, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary.
authors.forename: Bálint
authors.initials: B
authors.lastname: Botz
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary.
authors.forename: Teréz
authors.initials: T
authors.lastname: Bagoly
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary.
authors.forename: Erika
authors.initials: E
authors.lastname: Pintér
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Szolcsányi
mesh_terms: D000818:Animals; D000982:Antipruritics / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology*; D003243:Consciousness; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced; D009412:Nerve Fibers / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000139:chemically induced; D010455:Peptides / Q000494:pharmacology; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000187:drug effects*; D011984:Sensory Receptor Cells / Q000187:drug effects; D013004:Somatostatin / Q000097:blood
chemical_list: D000982:Antipruritics; D018377:Neurotransmitter Agents; D010455:Peptides; C029993:somatostatin-like peptides; D013004:Somatostatin; D002211:Capsaicin
keywords: Capsaicin-sensitive nociceptor; Counterirritation; Endogenous opioids; Somatostatin; TRPA1; TRPV1