Therapeutic Effects of Neurotrophic Factors GDNF and Artemin on Experimental Neuropathic Pain and Dorsal Root Injury

Abstract

Glial cell line derived neurotrophic factor (GDNF) and artemin maintain the structural and functional integrity of the adult nervous system and regulate the plasticity of the injured or diseased adult nervous system apparently by interacting with GFRalpha1/RET and GFRalpha3/RET systems.The clinical management of neuropathic pain is particularly challenging. Current therapies for neuropathic pain modulate nerve impulse propagation or synaptic transmission; these therapies provide limited efficacy due in part to dose-limiting and undesirable side effects. Here we show that chronic infusion of GDNF normalizes nerve injury-induced neurochemical changes and prevents the expression of neuropathic pain. Systemic artemin produces partial to complete normalization of multiple morphological and neurochemical features of the injury state.Damaged axons in the dorsal root of adult mammals rarely regrow into the spinal cord, leading to the permanent loss of sensory function. This continues to be a major unmet clinical challenge relevant to a host of disease and trauma-induced injuries to peripheral nerves. Here we show that systemic artemin restores sensory function, apparently permanently, in an experimental dorsal root injury model in rats, including responses to noxious heat, mechanical and chemical stimuli and sensory input-required proprioceptive responses of placement stabilization, targeting and grasping. These effects are likely to result from successful support of multiple classes of sensory afferents which cross the dorsal root entry zone into the spinal cord and make functional connections with spinal neurons. Delayed artemin treatment defines the "therapeutic window" for artemin application following injury to the nerve roots, indicating that this strategy may ultimately be of clinical benefit.Our results indicate that the behavioral symptoms of neuropathic pain states can be treated successfully, and that partial to complete reversal of associated morphological and neurochemical changes can be achieved with artemin. The damaged axons can re-grow perhaps into their original region of occupation, and make functional connections with spinal neurons, resulting in apparently permanent restoration of the lost sensory function following dorsal root injury. Our present studies provide experimental evidence that the neurotrophic factors GDNF and artemin may serve as clinically viable drugs in treating peripheral nerve injury or other neurodegenerative diseases.