Laboratory Investigation (2011) 91, 539-552; doi:10.1038/labinvest.2010.191;

published online 6 December 2010″
“Nerve growth factor (NGF) antagonism has long been proposed as a chronic pain treatment. In 2010, the FDA suspended clinical trials using tanezumab, a humanized monoclonal IPI-549 mw anti-NGF antibody, to treat osteoarthritis due to worsening joint damage in 16 patients. Increased physical activity in the absence of acute pain which normally prevents self-harm was purported as a potential cause. Such an adverse effect is consistent with an extension of tanezumab’s primary mechanism of action by decreasing pain sensitivity below baseline levels. In animal inflammatory pain models, NGF antagonism decreases intraepidermal nerve fiber (IENF) density and attenuates increases in expression of nociception-related proteins, such as calcitonin gene-related peptide (CGRP) and substance P (SP). Little is known of the effects of NGF WZB117 molecular weight antagonism in noninflamed animals and the hypoalgesia that ensues. In the current study, we immunized rats with NGF or cytochrome C (cytC) and examined

(1) nocifensive behaviors with thermal latencies, mechanical thresholds, the hot plate test, and the tail flick test, (2) IENF density, and (3) expression of CGRP, SP, voltage-gated sodium channel 1.8 (Nav1.8), and glutaminase in subpopulations of dorsal root ganglion (DRG) neurons separated by size and isolectin B4 (IB4) labeling. Rats with high anti-NGF titers had delayed responses on the

hot plate test but no other behavioral abnormalities. Delayed hot plate responses correlated with lower IENF density. CGRP and SP expression was decreased principally in medium (400-800 mu m(2)) and small neurons (<400 mu m(2)), respectively, regardless of IB4 labeling. Expression of Nav1.8 was only decreased in small and medium IB4 negative neurons. NGF immunization appears to result in a more profound antagonism of NGF than tanezumab therapy, but we hypothesize that decreases in IENF density and nociception-related protein expression are potential mechanisms buy Fedratinib for tanezumab-induced hypoalgesia. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.”
“The ion channel TRPA1 is activated by a wide variety of noxious stimuli, such as pollutants, products of oxidative tissue damage, and pungent natural products. Many TRPA1 activators are reactive electrophiles that form Michael adducts with cysteine and lysine residues of TRPA1′s intracellular N-terminus. Curcumin, the active principle of turmeric root (Curcuma longa), can also form Michael adducts.