title: Potential mechanisms for hypoalgesia induced by anti-nerve growth factor immunoglobulin are identified using autoimmune nerve growth factor deprivation.
abstract: 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.
authors.affiliation: Department of Anatomy and Cell Biology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Hoffman
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: M B
authors.initials: MB
authors.lastname: Anderson
authors.forename: R
authors.initials: R
authors.lastname: Schechter
authors.forename: K E
authors.initials: KE
authors.lastname: Miller
mesh_terms: D000367:Age Factors; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D045304:Cytochromes c / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D007136:Immunoglobulins / Q000009:adverse effects*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel; D020932:Nerve Growth Factor / Q000276:immunology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism; D013373:Substance P / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D006023:Glycoproteins; D007136:Immunoglobulins; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; D015222:Sodium Channels; C473590:isolectin B4-binding glycoprotein, mouse; D013373:Substance P; D045304:Cytochromes c; D020932:Nerve Growth Factor; C549319:tanezumab; D015740:Calcitonin Gene-Related Peptide