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Role of transient receptor potential vanilloid 1 receptors in adjuvant-induced chronic arthritis: in vivo study using gene-deficient mice.

Abstract
The transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel localized on a subset of primary sensory neurons and can be activated by a wide range of stimuli. The present study investigated the role of this receptor in chronic arthritis evoked by complete Freund's adjuvant (CFA) using TRPV1 receptor gene-deleted (TRPV1-/-) mice and wild-type counterparts (TRPV1+/+). In TRPV1+/+ mice, CFA injected intraplantarly into the left hindpaw and the root of the tail induced swelling of the injected and contralateral paws up to 130 and 28%, respectively, measured by plethysmometry throughout 18 days. Mechanonociceptive threshold measured with dynamic plantar aesthesiometry was decreased by 50 and 18% on the injected and contralateral paws, respectively. Histological examination and scoring of the tibiotarsal joints revealed marked arthritic changes in wild-type mice. In TRPV1-/- animals edema, histological score and mechanical allodynia were significantly smaller. Daily treatment with the lipoxygenase inhibitor nordihydroguaretic acid (NDGA), the cyclooxygenase inhibitor indomethacin, the bradykinin B2 receptor antagonist HOE-140 [D-arginyl-L-arginyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl-3-(2-thyenyl)-L-alanyl-L-seryl-D-1,2,2,4-tetrahydro-3-isoquinolinecarbonyl-L-(2a,3b,7ab)-octahydro-1H-indole-2-carbonyl-L-arginine], or the B1 receptor antagonist desArgHOE-140 [D-arginyl-L-arginyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl-3-(2-thyenyl)-L-alanyl-L-seryl-D-1,2,2,4-tetrahydro-3-isoquinolinecarbonyl-L-(2a,3b,7ab)-octahydro-1H-indole-2-carbonyl] was performed to reveal what mediators might activate TRPV1. NDGA significantly inhibited edema, hyperalgesia, and arthritis score in TRPV1+/+, but not in TRPV1-/- mice. The effect of indomethacin was markedly smaller in knockouts. In TRPV1+/+ animals, HOE-140, but not desArgHOE-140, inhibited arthritis, whereas in TRPV1-/- mice, HOE-140 produced limited effect. Thus, whereas bradykinin and lipoxygenase products seem to act exclusively via TRPV1 activation, prostanoids do not, or at least only partially, to enhance murine experimental arthritis and related hyperalgesia.
AuthorsArpád Szabó, Zsuzsanna Helyes, Katalin Sándor, Andrea Bite, Erika Pintér, József Németh, Agnes Bánvölgyi, Kata Bölcskei, Krisztián Elekes, János Szolcsányi
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 314 Issue 1 Pg. 111-9 (Jul 2005) ISSN: 0022-3565 [Print] United States
PMID15831443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cyclooxygenase Inhibitors
  • Enzyme Inhibitors
  • Lipoxygenase Inhibitors
  • Receptors, Drug
  • icatibant
  • Lipoxygenase
  • Prostaglandin-Endoperoxide Synthases
  • Bradykinin
  • Indomethacin
Topics
  • Animals
  • Arthritis, Experimental (genetics, pathology, physiopathology)
  • Bradykinin (analogs & derivatives, pharmacology, physiology)
  • Cyclooxygenase Inhibitors (pharmacology)
  • Edema (chemically induced, pathology)
  • Enzyme Inhibitors (pharmacology)
  • Hyperalgesia (genetics, physiopathology)
  • Indomethacin (pharmacology)
  • Joints (pathology)
  • Lipoxygenase (metabolism)
  • Lipoxygenase Inhibitors (pharmacology)
  • Male
  • Mechanoreceptors (drug effects)
  • Mice
  • Mice, Knockout
  • Pain Threshold (drug effects)
  • Prostaglandin-Endoperoxide Synthases (metabolism)
  • Receptors, Drug (antagonists & inhibitors, genetics, physiology)

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