Viral Vectors Encoding Endomorphins and Serine Histogranin Attenuate Neuropathic Pain Symptoms after Spinal Cord Injury in Rats

Abstract

BackgroundThe treatment of spinal cord injury (SCI)-induced neuropathic pain presents a challenging healthcare problem. The lack of available robust pharmacological treatments underscores the need for novel therapeutic methods and approaches. Due to the complex character of neuropathic pain following SCI, therapies targeting multiple mechanisms may be a better choice for obtaining sufficient long-term pain relief. Previous studies in our lab showed analgesic effects using combinations of an NMDA antagonist peptide [Ser1]histogranin (SHG), and the mu-opioid peptides endomorphins (EMs), in several pain models. As an alternative to drug therapy, this study evaluated the analgesic potential of these peptides when delivered via gene therapy.ResultsLentiviruses encoding SHG and EM-1 and EM-2 were intraspinally injected, either singly or in combination, into rats with clip compression SCI 2 weeks following injury. Treated animals showed significant reduction in mechanical and thermal hypersensitivity, compared to control groups injected with GFP vector only. The antinociceptive effects of individually injected components were modest, but the combination of EMs and SHG produced robust and sustained antinociception. The onset of the analgesic effects was observed between 1–5 weeks post-injection and sustained without decrement for at least 7 weeks. No adverse effects on locomotor function were observed. The involvement of SHG and EMs in the observed antinociception was confirmed by pharmacologic inhibition using intrathecal injection of either the opioid antagonist naloxone or an anti-SHG antibody. Immunohistochemical analysis showed the presence of SHG and EMs in the spinal cord of treated animals, and immunodot-blot analysis of CSF confirmed the presence of these peptides in injected animals. In a separate group of rats, delayed injection of viral vectors was performed in order to mimic a more likely clinical scenario. Comparable and sustained antinociceptive effects were observed in these animals using the SHG-EMs combination vectors compared to the group with early intervention.ConclusionsFindings from this study support the potential for direct gene therapy to provide a robust and sustained alleviation of chronic neuropathic pain following SCI. The combination strategy utilizing potent mu-opioid peptides with a naturally-derived NMDA antagonist may produce additive or synergistic analgesic effects without the tolerance development for long-term management of persistent pain.

Effect of carnosine, methylprednisolone and their combined application on irisin levels in the plasma and brain of rats with acute spinal cord injury

“…However, treatments remain limited, and are aimed mainly at supportive care due to the complex character of SCI (Nasirinezhad et al, 2015). Recent findings have indicated that SCI causes profound muscular atrophy, and bone loss with fragility.…”

“…Treatment is a challenging healthcare problem due to involvement of a complex cascade of secondary neurodegenerative events set in motion by the primary injury, coupled with the lack of available robust pharmacological and novel therapeutic approaches (Nasirinezhad et al, 2015). Glucocorticoid steroids, mainly methylprednisolone (MP), have been extensively used in the clinical treatment of spinal cord trauma beginning in the mid-1960s and throughout the 1970s.…”

Co-administration of human adipose-derived stem cells and low-level laser to alleviate neuropathic pain after experimental spinal cord injury

“…Various classes of drugs with analgesic characteristic are applied for treating neuropathic pain [7]. In addition to drug therapy, non-drug treatments for neuropathic pain such as surgery, acupuncture, transcutaneous electrical nerve stimulation, psychotherapy, and physiotherapy exist [2,[8][9][10][11][12][13]. Lowlevel laser therapy is one of the physiotherapy measures that can be taken for controlling neuropathic pain, and it has recently received much attention from researchers due to its low cost, being non-invasive and not having side effects [14,15].…”

Recombinant elastin-based nanoparticles for targeted gene therapy

“…Gene therapy that aims to deliver a gene of interest to replace, inactivate or correct the defective gene to help the diseased tissue function properly is the most promising approach for curing these debilitating genetic diseases. Scientists have used multiple gene delivery techniques such as lipid mediated gene delivery ( 4 ), cationic polymers ( 5 ), electroporation ( 6 ), microinjection ( 7 ), and viruses ( 8 ). Due to their efficient mode of gene delivery, viruses such as lentivirus are popular vectors for gene delivery ( 9 ).…”