Attenuation of mechanical hyperalgesia following spinal cord injury by administration of antibodies to nerve growth factor in the rat

Gwak, Young Seob; Nam, Taick Sang; Paik, Kwang Se; Hulsebosch, Claire E.; Leem, Joong Woo

doi:10.1016/s0304-3940(02)01251-x

Cited by 72 publications

(66 citation statements)

References 21 publications

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“…In the CCI model, an increase of NGF levels is observed in the cells of the injured area and in dorsal root ganglia at the level of the lesion, suggesting the involvement of NGF in the development of hyperalgesia in this model of neuropathic pain (24). Direct administration of NGF into the sciatic nerve induces hyperalgesia in rats (26), whereas NGF inhibition reduces thermal and mechanical hyperalgesia in CCI model (24,27,46), partial nerve transection (28) and partial transection of the spinal cord (47).…”

Section: Discussionmentioning

confidence: 97%

The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain

Ugolini¹,

Marinelli

Covaceuszach

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

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Nerve growth factor (NGF) is involved in pain transduction mechanisms and plays a key role in many persistent pain states, notably those associated with inflammation. On this basis, both the NGF ligand and its receptor TrkA (tyrosine kinase A) represent an eligible target for pain therapy. Although the direct involvement of NGF in pain modulation is well established, the effect of a direct functional block of the TrkA receptor is still unknown. In this study, we have demonstrated that MNAC13, the only anti-TrkA monoclonal antibody for which function neutralizing properties have been clearly shown both in vitro and in vivo, induces analgesia in both inflammatory and neuropathic pain models, with a surprisingly long-lasting effect in the latter. The formalin-evoked pain licking responses are significantly reduced by the MNAC13 antibody in CD1 mice. Remarkably, treatment with the anti-TrkA antibody also produces a significant antiallodynic effect on neuropathic pain: repeated i.p. injections of MNAC13 induce significant functional recovery in mice subjected to sciatic nerve ligation, with effects persisting after administration. Furthermore, a clear synergistic effect is observed when MNAC13 is administered in combination with opioids, at doses that are not efficacious per se. This study represents a direct demonstration that neutralizing antibodies directed against the TrkA receptor may display potent analgesic effects in inflammatory and chronic pain.analgesia ͉ behavior ͉ mice ͉ nerve growth factor

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Section: Discussionmentioning

confidence: 97%

The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain

Ugolini¹,

Marinelli

Covaceuszach

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

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“…Injury to the spinal cord results in an increased expression of NGF (Nakamura and Bregman, 2001), which acts to increase both neuropeptide expression and sprouting of nociceptive axons (Christensen and Hulsebosch, 1997;Gwak et al, 2003). The relative contribution by each of these potential mechanisms to the type and severity of pain is not known.…”

Section: Introductionmentioning

confidence: 99%

Semaphorin3A Inhibits Nerve Growth Factor-Induced Sprouting of Nociceptive Afferents in Adult Rat Spinal Cord

Tang¹,

Tanelian²,

Smith³

2004

J. Neurosci.

113

116

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Increased expression of NGF after spinal cord injury induces sprouting of primary nociceptive axons. Exogenous application of NGF also results in extensive sprouting of these axons and causes chronic pain in uninjured animals. During development, semaphorin3A is thought to act as a repulsive guidance cue for NGF-responsive nociceptive afferents, restricting their projections to the superficial dorsal horn. We investigated the ability of semaphorin3A to selectively reduce NGF-induced sprouting and neuropathic pain in adult rats. The chemorepulsive effect of virus-mediated semaphorin3A expression was shown to counteract the sprouting induced by NGF in a dosedependent manner, both in vitro and in adult rat spinal cords. Coexpression of semaphorin3A and NGF at moderate to low concentrations within the adult spinal cord reduced sprouting of calcitonin gene-related peptide and substance P-containing axons compared with GFP and NGF coexpression controls. At high expression levels of NGF, there was no difference in sprouting between the semaphorin3A-treated and control groups. The distribution of endogenous primary nociceptive afferents in the spinal cord appeared to be unaffected by semaphorin3A treatment in these experiments. Behavioral assessment shows that semaphorin3A coexpression with NGF led to decreased mechanical allodynia but no significant reductions in thermal hyperalgesia. These findings demonstrate directly that mature sensory afferents maintain their responsiveness to semaphorin3A, suggesting that this molecule might be used therapeutically to control aberrant sensory sprouting involved in pain or autonomic dysfunction.

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“…두 번째의 가능성은 척수손상 후 일차 구심성 신경섬 유들의 퇴화(degeneration)와 재생(regeneration)에 의해 형 성된 새로운 시냅스 회로가 척수 후각에서 형성된다는 것 이다 Gwak et al, 2003). 척수손상은 척수 후각에서 glutamate의 증가로 인 한 신경세포의 사멸(apoptosis or death)을 유발한다.…”

Section: 감각신호 전달 기전unclassified

“…(Hains et al, 2003;Gwak and Hulsebosch, 2005;McAdoo et al, 2005;Waxman, 2006, Liu et al, 2008). 세포내 작용기전 으로서는 cAMP, mitogen-associated protein kinase (MAPK), protein kinase C (PKC), protein kinase A (PKA), cAMP response element binding protein (CREB), calcium/calmodulin-dependent protein kinase (CaMKinase) 등의 활성화에 따른 전사와 번역과정의 활성화로 인한 해 당 단백질의 과발현 및 인산화 등 일련의 분자생물학적 인 반응들이 신경병증성 통증의 유발 및 유지에 관여하 는 것으로 보고되었다 (Crown et al, 2006;Labombarda et al, 2008;Lin et al, 2008 (Hains et al, 2003;Gwak et al, 2003;. 전기생리학적인 연구결과에 의하면, 척수손상 후 척수후각 신경세포들이 비유해성 자극이나 유해성 자극에 의해 과도하게 증가되 고 지속적인 반응을 보이는 것으로 알려지고 있는데 이 러한 상태를 척수후각 신경세포의 과흥분성 또는 중추성 감작이라고 한다 (Hains et al, 2003;Gwak et al, 2006;Crown et al, 2008) (Figure 1 (Chung et al, 1986;Dougherty et al, 199l;Gwak et al, 2008) (Hains et al, 2003;.…”

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Neuronal Hyperexcitability Mediates Below-Level Central Neuropathic Pain after Spinal Cord Injury in Rats

et al. 2010

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Spinal cord injury often leads to central neuropathic pain syndromes, such as allodynic and hyperalgesic behaviors. Electrophysiologically, spinal dorsal horn neurons show enhanced activity to non-noxious and noxious stimuli as well as increased spontaneous activity following spinal cord injury, which often called hyperexcitability or central sensitization. Under hyperexcitable states, spinal neurons lose their ability of discrimination and encoding somatosensory information followed by abnormal somatosensory recognition to non-noxious and noxious stimuli. In the present review, we summarize a variety of pathophysiological mechanisms of neuronal hyperexcitability for treating or preventing central neuropathic pain syndrome following spinal cord injury.Key words: Central neuropathic pain, hyperexcitability, rat model

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Attenuation of mechanical hyperalgesia following spinal cord injury by administration of antibodies to nerve growth factor in the rat

Cited by 72 publications

References 21 publications

The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain

The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain

Semaphorin3A Inhibits Nerve Growth Factor-Induced Sprouting of Nociceptive Afferents in Adult Rat Spinal Cord

Neuronal Hyperexcitability Mediates Below-Level Central Neuropathic Pain after Spinal Cord Injury in Rats

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