Antibodies to Nerve Growth Factor Reverse Established Tactile Allodynia in Rodent Models of Neuropathic Pain without Tolerance

Abstract

A considerable body of evidence implicates endogenous nerve growth factor (NGF) in conditions in which pain is a prominent feature, including neuropathic pain. However, previous studies of NGF antagonism in animal models of neuropathic pain have examined only the prevention of hyperalgesia and allodynia after injury, whereas the more relevant issue is whether treatment can provide relief of established pain, particularly without tolerance. In the current work, we studied the effects of potent, neutralizing anti-NGF antibodies on the reversal of tactile allodynia and thermal hyperalgesia in established models of neuropathic and inflammatory pain in rats and mice. In the complete Freund's adjuvant-induced hind-paw inflammation, spinal nerve ligation and streptozotocin-induced neuropathic pain models, a single intraperitoneal injection of a polyclonal anti-NGF antibody reversed established tactile allodynia from approximately day 3 to day 7 after treatment. Effects on thermal hyperalgesia were variable with a significant effect observed only in the spinal nerve ligation model. In the mouse chronic constriction injury (CCI) model, a mouse monoclonal anti-NGF antibody reversed tactile allodynia when administered 2 weeks after surgery. Repeated administration of this antibody to CCI mice for 3 weeks produced a sustained reversal (days 4 to 21) of tactile allodynia that returned 5 days after the end of dosing. In conclusion, NGF seems to play a critical role in models of established neuropathic and inflammatory pain in both rats and mice, with no development of tolerance to antagonism. Antagonists of NGF, such as fully human monoclonal anti-NGF antibodies, may have therapeutic utility in analogous human pain conditions.

A New Nerve Growth Factor-Mimetic Peptide Active on Neuropathic Pain in Rats

“…might be used as a therapy for neuropathic pain (Ro et al, 1999;Wild et al, 2007). Indeed, algesia is a known side effect of systemic and local applications of NGF even in clinical trials (Apfel, 2002).…”

A Synthetic Cell-Penetrating Peptide Antagonizing TrkA Function Suppresses Neuropathic Pain in Mice

“…Wild et al reported that a single dose of anti-NGF antibody, injected intraperitoneally 7 days after spinal nerve ligation in rats, started to suppress allodynia on day 2 after injection, and this persisted to day 7 after injection (18). Conversely, a single dose of IPTRK3, injected intraperitoneally 7 days after the PSNL, started to suppress both thermal hyperalgesia and mechanical allodynia at 1 h after injection, and this persisted to day 2 after injection in the present study.…”

“…Peripheral nerve injury causing neuropathic pain increases NGF levels at peripheral sites (16,17). Intraperitoneal injection of either anti-NGF antibody or anti-TrkA antibody after peripheral nerve injury reportedly suppresses neuropathic pain in rodents (18,19). The present study showed that IPTRK3, a cellpenetrating peptide that inhibits TrkA activity, produced anti-allodynic and anti-hyperalgesia effects on neuropathic pain in mice.…”

“…The superficial laminae are the sites of termination of afferents responding to noxious stimulation (C and Aδ), and the deep laminae are the sites of termination of non-nociceptive afferents responding to gentle touch (Aβ) (24). Mechanisms of the inhibitory effects of IPTRK3 on evoked Fos expression and mechanical allodynia might involve the suppression of the interaction between nociceptive and non-nociceptive afferents through TrkA (18).…”

Astrocytes and Chronic Pain Mechanisms—The Role of Histamine, IL-1β and NGF

“…NGF-mediated effects are central to inflammatory, surgical, visceral and neuropathic pain (1,9,25,26). In developing dorsal root ganglion neurons NGF stimulates local synthesis of cAMP-response-element-binding protein, leading to retrograde transport to the neural soma (5).…”