Abstract
The insufficient pain relief provided by current pharmacotherapy for chronic neuropathic pain is a serious medical problem. The enhanced glutamate signaling via NMDA receptors appears to be one of the key events in the development of chronic pain. Although effective, clinical use of systemic NMDA antagonists is limited by adverse effects such as hallucinations and motor dysfunction. Opioids are also potent analgesics but their chronic use is accompanied by tolerance and risk of addiction. However, combination of NMDA antagonists and opioids seems to provide a stable pain relieve at subthreshold doses of both substances, eliminating development of side effects. Our previous research showed that combined delivery of NMDA antagonist Serine histrogranin (SHG) and endomorphin1 (EM1) leads to attenuation of acute and chronic pain. The aim of this study was to design and evaluate an analgesic potency of the gene construct encoding SHG and EM1. Constructs with 1SHG copy in combination with EM1, 1SHG/EM1, and 6SHG/EM1 were intraspinally injected to animals with peripheral nerve injury-induced pain (chronic constriction injury, CCI) or spinal cord injury induced pain (clip compression model, SCI) and tactile and cold allodynia were evaluated. AAV2/8 particles were used for gene delivery. The results demonstrated 6SHG/EM1 as the most efficient for alleviation of pain-related behavior. The effect was observed up to 8 weeks in SCI animals, suggesting the lack of tolerance of possible synergistic effect between SHG and EM1. Intrathecal injection of SHG antibody or naloxone attenuated the analgesic effect in treated animals. Biochemical and histochemical evaluation confirmed the presence of both peptides in the spinal tissue. The results of this study showed that the injection of AAV vectors encoding combined SHG/EM constructs can provide long term attenuation of pain without overt adverse side effects. This approach may provide better treatment options for patients suffering from chronic pain.
Highlights
Chronic pain is a major complaint in patients with peripheral or central nerve injury (CruzAlmeida et al, 2005, 2009; Galluzzi, 2005; Taylor et al, 2010)
Animals exhibiting the presence of tactile and/or cold allodynia at the beginning of behavioral evaluation (1 week post Constriction Injury (CCI), 4 weeks post spinal cord injury model (SCI)) with paw withdrawal threshold values ≤8 and responses to acetone ≥50% were used in the subsequent experiments
CCI (Figures 1A,B) In the tactile allodynia test, animals treated with analgesic genes showed progressive increase in paw withdrawal threshold after the injection of the construct compared to control GFP group (F(df 3,18) = 1.449; P = 0.0068)
Summary
Chronic pain is a major complaint in patients with peripheral or central nerve injury (CruzAlmeida et al, 2005, 2009; Galluzzi, 2005; Taylor et al, 2010). Clinical and experimental studies have suggested several mechanisms contributing to the development of chronic pain and prospective targets for pharmacological intervention. Gene Therapy for Chronic Pain provide pain relief, the effects of exogenous pharmacologic agents are usually temporary. Long-term treatments for chronic pain may be limited in sustained effectiveness, dose escalation, development of tolerance and systemic side effects of medication during prolonged use. Contemporary treatment includes pharmacologic and psychological options, but are most appropriate in providing short-term relief (Finnerup and Baastrup, 2012; Yaksh et al, 2017). There is a need for improved therapeutic approaches for long-term management of chronic pain
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