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.
Subject(s)
Arthritis, Experimental/genetics , Arthritis, Experimental/physiopathology , Receptors, Drug/genetics , Receptors, Drug/physiology , Animals , Arthritis, Experimental/pathology , Bradykinin/analogs & derivatives , Bradykinin/pharmacology , Bradykinin/physiology , Cyclooxygenase Inhibitors/pharmacology , Edema/chemically induced , Edema/pathology , Enzyme Inhibitors/pharmacology , Hyperalgesia/genetics , Hyperalgesia/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 & inhibitorsABSTRACT
Activity-dependent adaptive changes in the nervous system involve structural and functional changes in the cortical circuitry. In this work the cortical function was studied by repeated recording of the somatosensory and motor potentials evoked by whisker deflections after altered sensory-motor experience in adult mice. The latencies of motor and somatosensory evoked potentials were found to shorten, while their amplitudes decreased, after a behavioural challenge involving the vibrissal apparatus. Sensory deprivation achieved by whisker trimming resulted in a partial reversal of the changes observed after increased activity. The derived parameters imply that cortical information processing speeds up as a result of experience, while decreased activity has the opposite effect. The methods used throughout the experiment were minimally invasive, and thus proved to be sufficient for the long-term follow-up of cortical functions.
