Emerging cell and molecular strategies for the study and treatment of painful peripheral neuropathies.

Pharmacologic treatment for the symptoms of painful neuropathy has been problematic, because there has been limited understanding of the underlying etiologies and systemic levels that an effective dose can have on multiple side effects. The use of molecular methods, such as gene deletion from knockout mice and cellular minipumps for delivery of biologic antinociceptive molecules, has led to a better understanding of the underlying mechanisms of the induction of intractable neuropathic pain. The initiation of an excitatory cascade after injury or disease leads to the induction of various second messenger systems, loss or down-regulation of the endogenous inhibitory spinal GABA system and central sensitization, causing such pain. The development and use of cellular minipumps, immortalized cell lines bioengineered to secrete various antinociceptive molecules for the reversal of neuropathic pain, makes cellular therapy a strategy for clinical use in the next few years. The development of molecular "disimmortalization" technologies will make the use of such engineered cell lines safe for human use. Direct somatic gene transfer for neuropathic pain will eventually overcome the problems associated with transplantation of non-autologous and xenogenic cells. These virus-mediated methods, although at the early stages of evolution and use, offer large-scale production of biologic agents that can be conveniently and confidently used for the long-term relief of chronic neuropathic pain in a clinical setting, without systemic effects or surgical interventions.