The direction of glutamate transport by the cell membrane tr

The direction of glutamate transport by the cell membrane transporter is reversible. As mentioned above, glutamate transport is an electrogenic process associated with a transmembrane ion gradient established by the Na+-K+ pump through hydrolysis of adenosine triphosphate. Under conditions of energy depletion, an outward release, that is a reversed uptake of glutamate can occur (Szatkowski et al., 1990). This phenomenon produced by inversely operating glutamate transporter may be a dominant mechanism of glutamate release in vinorelbine synthesis ischemia and spinal cord trauma (Li et al., 1999, Phillis et al., 2000). In vitro ischemia-induced release of glutamate was abolished by blocking the glutamate transporter using TBOA or preloading tPDC (Anderson et al., 2001, Roettger and Lipton, 1996). Our data are consistent with these reports and suggest that glutamate release during the formalin test also occurs through the inversely operating glutamate transporter. It is possible that increased energy demand in the spinal cord in pathological pain states may cause ATP consumption and disturbed energy metabolism, which might reverse the operation of the spinal glutamate transporter in the inflammatory pain model (Tao et al., 2005). Aside from ATP consumption conditions, the driving force for glutamate uptake may be decreased when extracellular [Na+] / intracellular [K+] decreases and/or intracellular [Na+] / extracellular [K+] increases (Grewer et al., 2008). These states will also result in reversal of the glutamate transport direction. Accordingly, Grewer et al. (Grewer et al., 2008) suggested that a sudden decrease in the driving force for uptake, caused by glutamate receptor-induced depolarization of the postsynaptic membrane, may result in the release of significant amounts of glutamate. However, the mechanisms underlying the uptake reversal of the glutamate transporter in the inflammatory pain model cannot be determined from the current study and remain to be investigated further. Nevertheless, our results are relevant to a greater understanding of glutamate release and the contribution of the glutamate transporter in the inflammatory pain model. In the current study, tPDC showed antinociceptive effects in the formalin test despite increasing extracellular glutamate. We investigated the mechanism of the literally paradoxical effect of tPDC by pretreating with antagonists of various receptors, among which only the α-2 adrenergic receptor was shown to be connected. Thus, the antinociceptive effect of tPDC may be associated with noradrenergic activation, mediated by glutamatergic neurons, which are a major source of excitatory input to monoaminergic cell bodies in the brainstem (Somogyi and Llewellyn-Smith, 2001). However, the antinociception produced by tPDC was only partially reversed when pretreated with yohimbine. Although this could result from an insufficient dose of the antagonists, other mechanisms such as postsynaptic glutamate receptor desensitization and disturbance in the glutamate/glutamine cycle in spinal glia may also be involved in mediating tPDC-induced analgesia. Another possible mechanism may be excitotoxicity resulting from an excessive increase in extracellular glutamate by heteroexchange following tPDC administration. However, no significant difference in the apoptotic cell count was observed between saline- and tPDC-treated rats in the formalin test. This suggests that antinociception exhibited by tPDC is not associated with neurotoxicity.
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Conflicts of interest
Acknowledgments This study was supported by grants from the Chonnam National University Hospital Biomedical Research Institute (CRI14005-1) and from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2012R1A1A1004608), South Korea.
Introduction ATP binding cassette transporters shuttle biological materials in and out of cells in an ordered, energy dependent fashion. Humans are multicellular organisms that have 48 separate genes that code for such transporters and these have been classified into seven distinct families designated by the nomenclature ABCA-G [1]. Within the ABCA family there are twelve examples that are split into two subgroups, where ABCA1 and ABCA2 share homology and represent among the largest of the family (∼270kD; [2]). The importance of each of these in human disease [3] has been established through the analysis of multiple SNPs and genetic mutations. Interestingly, Pubmed searches for publications that carry ABCA1 in their title have reached approximately 1000, while for ABCA2 the number is presently less than 50. To some degree this reflects the initial publication that reported linkage of ABCA1 mutations with Tangier disease, a cholesterolemia that causes high levels of morbidity and mortality in young adults in isolated island geography [4].