Analgesic Effect of Recombinant GABAergic Cells in a Model of Peripheral Neuropathic Pain

Abstract

Chronic neuropathic pain represents a clinically challenging state with a poor response to current treatment options. Long-term management of chronic pain is often associated with the development of tolerance, addiction, and other side effects, reducing the therapeutic value of treatment. Alternative strategies based on cell therapy and gene manipulation, balancing the inhibitory and excitatory events in the spinal cord, may provide sustained pain relief in the long term. Transplantation of GABAergic cells has been successfully used to enhance inhibition and to restore physiological spinal pain processing. However, since the underlying mechanism of chronic pain development involves changes in several pain-signaling pathways, it is essential to develop an approach that targets several components of pain signaling. Recombinant cell therapy offers the possibility to deliver additional analgesic substances to the restricted area in the nervous system. The current study explores the analgesic potential of genetically modified rat embryonic GABAergic cells releasing a peptidergic NMDA receptor antagonist, Serine 1 -histogranin (SHG). Overactivation of glutamate NMDA receptors contributes to the hyperexcitability of spinal neurons observed in chronic pain models. Our approach allows us to simultaneously target spinal hyperexcitability and reduced inhibitory processes. Transplantable cells were transduced by viral vectors encoding either one or six copies of SHG cDNAs. The analgesic potential of recombinant cells after their intraspinal transplantation was evaluated in a model of peripheral nerve injury. Enhanced reduction of hypersensitivity to thermal and mechanical stimuli was observed in animals treated by recombinant cells compared to the nonrecombinant group. The recombinant peptide was detected in the spinal tissue, suggesting its successful production by transplanted cells. Our results demonstrate the feasibility of using recombinant cells releasing adjunct analgesic peptides in the therapy of neuropathic pain.

The efficacy of GABAergic precursor cells transplantation in alleviating neuropathic pain in animal models: a systematic review and meta-analysis

“…One thousand seven hundred twenty one studies were excluded by screening the titles and abstracts and the full texts of the remaining 39 were studied (Appendix 2). Finally, the data of 13 studies were included in the present meta-analysis [ 15 , 16 , 22 - 32 ] ( Fig. 1 ).…”

“…The route of administration was also evaluated in in the present study. Overall, the method of injection was intraspinal in nine studies [ 15 , 22 - 24 , 26 , 27 , 29 , 30 , 32 ] and intrathecal in three studies, while one study had transplanted the cells in the anterior cingulate cortex. Overall, the analyses revealed that the intraspinal administration method might be the desired route for the transplantation of GABAergic cells.…”

“…Recent findings emphasize on the favorable effects of using these cells in alleviating chronic pain. Moreover, injection of these cells has improved and reduced neuropathic pain in animal models [ 14 - 16 ].…”

Calcium Signaling in Vertebrate Development and Its Role in Disease

“…These cells were then transplanted onto an injury site in order to assess their effect on peripheral neuropathic pain after 1 week of induced injury in rat spinal cord. This transplant resulted in improved pain sensitivity based upon a pain-related behavioral assessment with four pain parameters: mechanical, heat, cold, and tactile [ 143 ]. Similarly, Mery et al engineered pacemaker cells from embryonic stem cells that induce InsP3 mediated oscillatory calcium release from the endoplasmic reticulum; these cells had a potential to serve as pacemaker cells prior to the development of pacemaker ionic channels in early embryos.…”

Experimental Gene Therapy with Serine-Histogranin and Endomorphin 1 for the Treatment of Chronic Neuropathic Pain

“…Previous studies have shown that the naturally occurring peptide histogranin (Lemaire et al, 1993 ) and its stable analog Serine-Histogranin (SHG) have NMDA receptor antagonist activity and do not interfere with locomotion (Lemaire et al, 1995 ; Prasad et al, 1995 ; Hama et al, 1999 ; Hama and Sagen, 2002 ; Hentall et al, 2007 ). Furthermore, data has shown marked attenuation of hyperalgesia and allodynia with the spinal introduction of SHG through intrathecal injection or via cell or gene therapy (Siegan et al, 1997 ; NasiriNezhad and Sagen, 2005 ; Gajavelli et al, 2008 ; NasiriNezhad et al, 2015 ; Jergova et al, 2016a , b ).…”