Local Nogo-66 administration reduces neuropathic pain after sciatic nerve transection in rat

Neuropathic pain after periphery nerve injury is frequently accompanied by the regeneration of the injured nerve fibers. We tested in this study whether local administration of Nogo-66, a well-studied axon growth inhibiting peptide in the central nerve system, could reduce the pain related behavior after sciatic nerve transection in rat. Nogo-66 peptide was purified as a GST fusion protein. Its inhibitory function was testified by neurite outgrowth assay of primary cultured neurons, and then it was given directly at the lesion site by a minipump for 2 weeks. Mechanical nociceptive withdrawal responses and heat hyperalgesia responses were assessed during a 4-week period, and autotomy was evaluated during a 6-week period. The results showed that the mechanical allodynia and heat hyperalgesia scores of the rats treated with GST-Nogo-66 were significantly higher than the controls between 7 and 14 days after sciatic nerve transection. The autotomy scores in the GST-Nogo-66 group were significantly lower than the controls from 28 days after surgery. Taken together, the results of our present study suggest that Nogo-66 may be utilized to decrease the neuropathic pain after periphery nerve injury.

[1]  Kouhei Tsumoto,et al.  Practical considerations in refolding proteins from inclusion bodies. , 2003, Protein expression and purification.

[2]  P. Wall.  The Painful Consequences of Peripheral Injury , 1984, Journal of hand surgery.

[3]  A. B. Huber,et al.  Nogo-A Inhibits Neurite Outgrowth and Cell Spreading with Three Discrete Regions , 2003, The Journal of Neuroscience.

[4]  P. D. Wall,et al.  Autotomy following peripheral nerve lesions: experimental anesthesia dolorosa , 1979, Pain.

[5]  Fumio Nakamura,et al.  Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein , 2000, Nature.

[6]  Z. Seltzer,et al.  Comparison of autotomy behavior induced in rats by various clinically-used neurectomy methods , 2000, Pain.

[7]  S. David,et al.  A Role for Nogo Receptor in Macrophage Clearance from Injured Peripheral Nerve , 2007, Neuron.

[8]  W. Kingery,et al.  The resolution of neuropathic hyperalgesia following motor and sensory functional recovery in sciatic axonotmetic mononeuropathies , 1994, Pain.

[9]  Marco Domeniconi,et al.  Overcoming inhibitors in myelin to promote axonal regeneration , 2005, Journal of the Neurological Sciences.

[10]  W. Kingery,et al.  Adjacent neuropathic hyperalgesia in rats: A model for sympathetic independent pain , 1991, Neuroscience Letters.

[11]  L. Ro,et al.  Effect of NGF and anti-NGF on neuropathic pain in rats following chronic constriction injury of the sciatic nerve , 1999, PAIN.

[12]  D. Tanelian,et al.  Semaphorin3A Inhibits Nerve Growth Factor-Induced Sprouting of Nociceptive Afferents in Adult Rat Spinal Cord , 2004, The Journal of Neuroscience.

[13]  S. Strittmatter,et al.  Nogo-C is sufficient to delay nerve regeneration , 2003, Molecular and Cellular Neuroscience.

[14]  Martin E. Schwab,et al.  Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1 , 2000, Nature.

[15]  D. Tracey,et al.  Depletion of macrophages reduces axonal degeneration and hyperalgesia following nerve injury , 2000, Pain.

[16]  G. Lewin,et al.  Neurotrophins, nociceptors and pain , 2000, Current opinion in anaesthesiology.

[17]  M. Schwab,et al.  Nogo-A expressed in Schwann cells impairs axonal regeneration after peripheral nerve injury , 2002, The Journal of cell biology.

[18]  Sophie Pezet,et al.  Neurotrophins: mediators and modulators of pain. , 2006, Annual review of neuroscience.

[19]  W. Kingery,et al.  The development of chronic mechanical hyperalgesia, autotomy and collateral sprouting following sciatic nerve section in rat , 1989, Pain.

[20]  J. Castellote,et al.  A loose ligature-induced mononeuropathy produces hyperalgesias mediated by both the injured sciatic nerve and the adjacent saphenous nerve , 1993, Pain.

[21]  B. Pomeranz,et al.  Spread of saphenous somatotopic projection map in spinal cord and hypersensitivity of the foot after chronic sciatic denervation in adult rat , 1984, Brain Research.