TRPV1 and CB sub(1) receptor-mediated effects of the endovanilloid/endocannabinoid N-arachidonoyl-dopamine on primary afferent fibre and spinal cord neuronal responses in the rat

• Published in: The European journal of neuroscience 2004-07, Vol.20 (1), p.175-184
• Main Authors: Sagar, DR, Smith, P A, Millns, P J, Smart, D, Kendall, DA, Chapman, V
• Format: Article
• Language: English
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2004.03481.x

N-arachidonoyl-dopamine (NADA) is an endogenous ligand at TRPV1 and CB sub(1) receptors, which are expressed on primary afferent nociceptors. The aim of this study was to determine contributions of proposed pronociceptive TRPV1 and antinociceptive CB sub(1) receptors to effects of peripheral NADA on primary afferent fibre function. Effects of NADA on primary afferent nociceptor function, determined by whole cell patch clamp and calcium imaging studies of adult dorsal root ganglion (DRG) neurons, were determined. Application of NADA (1 mu m) to DRG neurons depolarized the resting membrane potential (Vm) from -58 plus or minus 1 to -44 plus or minus 3 mV (P < 0.00001) and evoked a significant increase (P < 0.0001) in intracellular calcium (74 plus or minus 11% of response to 60 mm KCl), compared to basal. The TRPV1 receptor antagonist capsazepine abolished NADA-evoked depolarization of Vm (P < 0.0001) and NADA-evoked calcium responses (P < 0.001), which were also blocked by the CB sub(1) receptor antagonist SR141716A (P < 0.001). Effects of NADA (1.5 mu g and 5 mu g/50 mu L) on mechanically evoked responses of dorsal horn neurons in anaesthetized Sprague-Dawley rats were studied. Intraplantar injection of the higher dose of NADA (5 mu g/50 mu L) studied significantly inhibited innocuous (8, 10 g) mechanically evoked responses of dorsal horn neurons compared to vehicle, effects blocked by intraplantar injection of SR141716A. Higher weight (26-100 g) noxious-evoked responses of dorsal horn neurons were also significantly inhibited by NADA (5 mu g/50 mu L), effects blocked by intraplantar injection of the TRPV1 antagonist, iodo-resiniferatoxin. NADA has a complex pattern of effects on DRG neurons and primary afferent fibres, which is likely to reflect its dual site of action at TRPV1 and CB sub(1) receptors and the differential expression of these receptors by primary afferent fibres.