Targeting glutamate and opioid signaling by gene therapy in spinal cord injury-induced pain in rats

Low efficacy of current pharmacotherapy for chronic neuropathic pain demands search for novel therapeutic targets and approaches. Enhanced glutamate signaling through NMDA receptors is one of the hypothesized mechanisms underlying development of neuropathic pain. However, although effective in animal models, clinical use of NMDA antagonists is limited by adverse effects such as hallucinations and motor dysfunction. Opiates have also been used in treatment of chronic pain with various successes, mostly due to unwanted side effects. Previous studies in our lab have shown NMDA antagonists activity of serine-histogranin (SHG), a synthetic analog of naturally occurring histogranin, lacking adverse effect. Transplantation of recombinant rat neuronal progenitors transduced with SHG construct reduced hypersensitivity induced by peripheral nerve injury. In addition, SHG can enhance opioid antinociceptive potency, thus reducing opioid doses and attendant side effects. Endomorphins (EMs) are endogenous opioid peptides with high selectivity for μ-opioid receptors. The aim of this study was to evaluate the antinociceptive potency of combined gene therapy with hexSHG (a 6 copy multi-SHG construct) and EM1 genes in rats with neuropathic pain symptoms. Spinal cord clip compression was used to induce central neuropathic pain. Five weeks post injury, lenti-hexSHG recombinant cells or lenti–EM1 constructs were intraspinally injected. Reduction of tactile and cold allodynia was observed in both groups of rats and analgesic effects were attenuated by SHG antibody or naloxone respectively. To evaluate combined therapy, SHG peptide was intrathecally delivered to lenti-EM1 injected animals at 7 weeks post injury. This further reduced tactile and cold allodynia compared to EM1-only treated animals. Intraspinal injection of both lenti-plasmids together nearly completely abolished cold allodynia and modestly attenuated tactile allodynia. These results encourage us to engineer compound constructs encoding both SHG and EM1 peptides in order to achieve better long-term analgesic outcomes in management of chronic neuropathic pain. Supported by NS51667 and CNF 190926.