Article Commentary: Transplants of Neuronal Cells Bioengineered to Synthesize GABA Alleviate Chronic Neuropathic Pain

Abstract

The use of cell lines utilized as biologic "minipumps" to provide antinociceptive molecules, such as GABA, in animal models of pain is a newly developing area in transplantation biology. The neuronal cell line, RN33B, derived from E13 brain stem raphe and immortalized with the SV40 temperature-sensitive allele of large T antigen (tsTag), was transfected with rat GAD67 cDNA (glutamate decarboxylase, the synthetic enzyme for GABA), and the GABAergic cell line, 33G10.17, was isolated. The 33G10.17 cells transfected with the GAD67 gene expressed GAD67 protein and synthesized low levels of GABA at permissive temperature (33 degrees C), when the cells were proliferating, and increased GAD67 and GABA during differentiation at nonpermissive temperature (39 degrees C) in vitro, because GAD67 protein expression was upregulated with differentiation. A control cell line, 33V1, transfected with the vector alone, contained no GAD67 or GABA at either temperature. These cell lines were used as grafts in a model of chronic neuropathic pain induced by unilateral chronic constriction injury (CCI) of the sciatic nerve. Pain-related behaviors, including cold and tactile allodynia and thermal and tactile hyperalgesia, were evaluated after CCI in the affected hind paw. When 33G10.17 and 33V1 cells were transplanted in the lumbar subarachnoid space of the spinal cord 1 week after CCI, they survived greater than 7 weeks on the pia mater around the spinal cord. Furthermore, the tactile and cold allodynia and tactile and thermal hyperalgesia induced by CCI was significantly reduced during the 2-7-week period after grafts of 33G10.17 cells. The maximal effect on chronic pain behaviors with the GABAergic grafts occurred 2-3 weeks after transplantation. Transplants of 33V1 control cells had no effect on the allodynia and hyperalgesia induced by CCI. These data suggest that a chronically applied, low local dose of GABA presumably supplied by transplanted cells near the spinal dorsal horn was able to reverse the development of chronic neuropathic pain following CCI. The use of neural cell lines that are able to deliver inhibitory neurotransmitters, such as GABA, in a model of chronic pain offers a novel approach to pain management.

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

“…light touch). Moreover, intrathecal administration of GABA, GABA A , or GABA B receptor agonists following peripheral nerve injury has been shown to reduce neuropathic pain (Eaton et al, 1999a(Eaton et al, , 1999bAsiedu et al, 2010;Munro et al, 2010). Thus, there is adequate evidence to suggest that hyperalgesia and allodynia after nerve injury are a result of impaired inhibitory neurotransmission and/or dysfunctional GABA-ergic inter-neurons in the dorsal horn of the spinal cord (Moore et al, 2002).…”

“…However, systemic administration of GABA-enhancing drugs is not efficacious for relieving neuropathic pain, as it cannot specifically improve inhibitory neurotransmission in the spinal cord and is associated with significant side effects. Therefore, the idea of grafting of GABA-secreting cells or GABA-ergic neurons directly into the spinal cord has received considerable interest in neuropathic pain models (Eaton et al, 1999a(Eaton et al, , 1999b(Eaton et al, , 2007Mukhida et al, 2007).…”

Transgenic overexpression of galanin in the dorsal root ganglia modulates pain-related behavior

“…Similarly, several studies have shown that intrathecal galanin significantly reduces allodynia induced by chronic constriction injury (6,34,35). In addition, Eaton et al (36) have shown that a spinal cord implant of genetically modified cells that secrete galanin significantly reduces allodynia after chronic constriction injury.…”

Transplantation of GABAergic Neurons from ESCs Attenuates Tactile Hypersensitivity Following Spinal Cord Injury

“…the subarachnoid space shows an improvement of pain-like responses induced by injury to the peripheral nerve [14,15]. A subarachnoid transplant of the carcinoma-derived neuronal cell line that secretes GABA attenuates pain-like responses following SCI [16].…”