ÿþAlthough ASIC3 seems to predominate in the mediation of pain signals asics gel lyte from the periphery, ASIC1 or composite ASIC1/2 channels may have a more important role in pain sensation in the central nervous system (CNS). ASICs are expressed in the CNS in multiple locations including hippocampus, hypothalamus, midbrain, and cerebellum ( 6 , 215 , 274 , 307 ). While not all of these locations are involved in pain sensing, it is likely that ASICs identified in neurons of the dorsal horn are responsible for integrating peripheral pain signals before transmission to the cortex ( 32 ).

In general, and despite data from knockout animals, a reasonable case can be made for ASICs, particularly ASIC3, being attractive targets for novel analgesic strategies. Acid-induced pain in humans was attenuated by treatment with amiloride ( 392 ), suggesting that inhibitors of ASICs, potentially including peptide toxins and aminoglycoside antibiotics ( 145 ), in addition to the more conventional amiloride and NSAID analogs ( 128 ), could play a asics gel nimbus role in the treatment of pain, while avoiding the behavioral issues associated with opiates ( 272 ). A more detailed account of the literature surrounding the role of ASICs in pain is provided in an excellent recent review ( 98 ).

Studies of ASIC1 in mice have implicated it in synaptic plasticity, learning, and memory formation asics tigers (409 411). In the CNS, the protein appears to localize with the postsynaptic density-95 protein (PSD-95), which likely targets ASIC1 to areas of high synaptic density ( 409 , 410 ). Behavioral tests of mice overexpressing ASIC1 found increased acquired fear related behavior ( 411 ), while ASIC1 knockout mice showed a deficit in cued and contextual fear conditioning ( 409 ), suggesting that perhaps ASIC1 could play a role in anxiety or fear learning. Interestingly, it has recently been reported that decreased brain pH resulting from hypercarbia also elicits fear in mice, a behavioral response that is attenuated by ASIC1 knockout ( 442 ).

For example, during ischemic stroke asics trainers mens there is a localized reduction in the extracellular pH. This acidosis is hypothesized to activate homomeric ASIC1 channels, leading to elevations of intracellular calcium and cell death. As noted earlier, the P Na /P Ca 2 for homotrimeric rat ASIC1a has been calculated as 2.5 by one group and as 18.5 by another group ( 33 , 405 ). The divergence between these two values is likely due to the difficulties with calculating the permeability for a channel that is allosterically modulated by the divalent cation in question as well as the innate kinetics of the channel, making it difficult to record accurate measurements ( 23 , 38 , 94 , 142 , 195 , 300 ).

While there is debate over the P Ca 2 of homotrimeric ASIC1 channels, it has been shown that cells expressing homotrimeric rat ASIC1a can respond to an acidic pH pulse with an increase in cytosolic calcium ( 429 ). This increase is due to extracellular calcium influx, as it still occurs after the endoplasmic reticulum is emptied by thapsigargin, and is sensitive to amiloride ( 429 ). This increase in calcium is postulated to lead to increased cell death secondary to acidosis; cells expressing rat ASIC1a are more sensitive to cell damage by incubation in pH 5.0 medium than cells without the ion channel as measured by a lactate dehydrogenase release assay asics womens running shoes ( 429 ).

This could not be accounted for by simple neuronal death as treatment with diazepam and pentobarbital, which protect neurons, did not prevent the loss of ASIC message. ASIC1a expression was also reduced, but in a more restricted area. A more recent functional study has demonstrated that ASIC1 activity is, however, important in seizure termination, as seizures in ASIC1 knockout mice were much more severe than in their wild-type counterparts; similar results were obtained when ASIC1 was acutely inhibited in wild-type mice by intracranial injection of PcTx1 ( 443 ). Conversely, overexpression of ASIC1 shortened seizure duration.