Role of low-affinity nerve growth factor receptor inhibitory antibody in reducing pain behavior and calcitonin gene-related Peptide expression in a rat model of wrist joint inflammatory pain.
OBJECTIVE
Nerve growth factor (NGF), via the high-affinity receptor, tyrosine kinase A, has been widely reported as a mediator of pain caused by inflammation. A clinical trial has suggested that anti-NGF antibody is effective for pain caused by osteoarthritis of the knee. However, adverse events such as headache (8.9%), upper respiratory tract infection (7.3%), and paresthesia (6.8%) were reported. We hypothesized that inhibition of the low-affinity NGF receptor, p75 neurotrophin receptor (p75NTR), is also effective for joint pain and may reduce side effects. This study examined suppression of pain behavior and expression of pain-inducing neuropeptides such as calcitonin gene-related peptide (CGRP) and p75NTR in dorsal root ganglia neurons by a p75NTR inhibitory antibody in a rat model of wrist joint inflammatory pain.


METHODS
We injected complete Freund's adjuvant (CFA) into the wrist joint of rats and used this as a model of inflammatory pain. We applied 10 microL of saline (CFA + saline group; n = 20) or 1, 10, or 50 microL of a p75NTR inhibitory antibody (CFA + p75NTR inhibitory antibody group; n = 40) directly to the inflamed joint in the rats. Mechanical hyperalgesia was measured for 2 weeks using von Frey filaments. We assessed CGRP and p75NTR expression in C8 dorsal root ganglia immunochemically. Adverse events such as loss of weight and/or appetite, constipation, and infection were examined.


RESULTS
p75NTR inhibitory antibody reduced mechanical hyperalgesia caused by CFA (p<.05 vs controls) in the rat model (p<.01 vs saline), without any adverse events. We found that 10 and 50 microL of a p75NTR inhibitory antibody were more effective for pain, without a significant difference between doses. CGRP and p75NTR immunoreactivity was upregulated in the CFA + saline groups compared with a control group (p<.01). However, direct p75NTR inhibitory antibody application decreased CGRP and p75NTR expression after wrist inflammation (p<.01).


CONCLUSIONS
p75NTR inhibition may be a therapeutic target for inflamed joint pain treatment with reduced adverse events.
Iwakura
Nahoko
N
Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. niwakura@qf7.so-net.ne.jp
Ohtori
Seiji
S
Orita
Sumihisa
S
Yamashita
Masaomi
M
Takahashi
Kazuhisa
K
Kuniyoshi
Kazuki
K
D000818:Animals; D018771:Arthralgia / Q000188:drug therapy* / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000494:pharmacology*; D007270:Injections, Intra-Articular; D008297:Male; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors*; D012016:Reference Values; D012680:Sensitivity and Specificity; D014955:Wrist Joint / Q000187:drug effects* / Q000503:physiopathology
D020800:Receptor, Nerve Growth Factor; D005620:Freund's Adjuvant; D015740:Calcitonin Gene-Related Peptide