1. ¹Department of Neurology, University of Michigan, and VA Ann Arbor Healthcare Systems, Ann Arbor, MI, USA
2. ²Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA

Correspondence: Dr DJ Fink, Department of Neurology, University of Michigan Health System, 1500 E. Medical Center Drive, Room 1914 Taubman Center, Ann Arbor, MI 48109-0316, USA. E-mail: djfink@umich.edu

Received 19 October 2006; Revised 15 February 2007; Accepted 16 February 2007; Published online 19 April 2007.

Abstract

We examined the role of spinal tumor necrosis factor-alpha (TNF) in neuropathic pain of peripheral nerve origin. Two weeks after selective L5 spinal nerve ligation (SNL), rats exhibiting mechanical allodynia and thermal hyperalgesia showed a marked increase in full-length membrane-associated TNF (mTNF) in the dorsal horn of spinal cord, in the absence of detectable soluble TNF peptide. Local release of the soluble p55 TNF receptor, achieved by herpes simplex virus vector-based gene transfer to dorsal root ganglion, resulted in a reduction of mTNF and concomitant reductions in interleukin-1 and phosphorylated p38 MAP kinase. Subcutaneous inoculation of soluble p55 TNF receptor expressing HSV vector into the plantar surface of the hind foot ipsilateral to the ligation 1 week before SNL delayed the development of both mechanical allodynia and thermal hyperalgesia; subcutaneous inoculation into the hind foot ipsilateral to the ligation 1 week after SNL resulted in a statistically significant reduction in mechanical allodynia and thermal hyperalgesia that was apparent 1 week after inoculation. These results suggest a novel 'reverse signaling' through glial mTNF, which may be exploited to downregulate the neuroimmune reaction in spinal cord to reduce chronic neuropathic pain.