Antinociceptive effect of recombinant neuroprogenitor intraspinal transplants in models of peripheral and central neuropathic pain

Abstract

Hypothesized mechanisms underlying chronic neuropathic pain following injury to the peripheral or central nervous system include increased hyperexcitability of spinal dorsal horn neurons due to loss or dysfunction of inhibitory γ-aminobutyric acid (GABA)-ergic interneurons, and enhanced excitatory glutamate signaling through NMDA receptors. Restoration of inhibitory tone and/or reduction of hyperexcitability via transplantation of selected cell types is a potential long-term intervention. The use of a recombinant neuronal progenitor cell (NPC) approach targeting GABA and glutamatergic signaling was evaluated in these experiments. Pre-differentiated rat GABAergic NPCs were intraspinally injected into rats with peripheral nerve injury-induced pain using sciatic nerve injury model. An improvement in behavioral outcome was observed for mechanical hyperalgesia and cold allodynia. Concurrent intrathecal injection of serine-histogranin (SHG), an NMDA antagonist, enhanced the analgesic effect of grafted cells. In accordance with behavioral data we found decreased number of c-Fos positive neurons in the superficial dorsal horn laminae in SHG treated rats, suggesting attenuated injury-induced excitation of nociceptive spinal neurons. For site-specific release of SHG a recombinant NPC capable of releasing GABA and SHG were engineered and intraspinally transplanted into rats after peripheral nerve injury. An markedly enhanced attenuation of cold allodynia and modestly attenuated mechanical hyperalgesia were observed. Intraspinal injection of GABAergic NPC was also used in the clip compression model of below-level pain after spinal cord injury. Beneficial effects in reducing tactile and cold allodynia were observed for several weeks post grafting. Our results suggest that transplantation of GABAergic NPC can attenuate peripheral and central nerve injury-induced chronic pain and that enhancement of this approach could be achieved by genetic modification of grafted cells. Supported by NS51667.