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 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 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 μm(2)) and small neurons (<400 μm(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 for tanezumab-induced hypoalgesia.