| Budget Amount *help |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
1. To clarify the supraspinal mechanism of action of gabapentin, whole-cell patch-clamp recordings were performed on locus coeruleus (LC) neurons in brainstem slices prepared from mice after peripheral nerve injury or mice subjected to a sham operation, and the effects of gabapentin on synaptic transmission were studied. Gabapentin (10-100 μM) concentration-dependently reduced the GABAAreceptor-mediated IPSCs in slices prepared from partial nerve-ligated mice (the Seltzer mode)), whereas glutamate-mediated EPSCs were hardly affected. By contrast, gabapentin did not reduce IPSCs in slices taken from mice given a sham operation. Since gabapentin reducedIPSCs together with an increase in the paired-pulse ratio, it acts on the presynaptic GABAergic nerve terminals in the LC. Moreover, the protein kinase A inhibitor 11-89 but not the protein kinase C inhibitor chelerythrine abolished the inhibitory action of gabapentin on IPSCs, suggesting that PICA-mediated phosphorylation seems to be impo
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rtant for supraspinal gabapentin responsiveness in neuropathic conditions.Together, gabapentin generates PICA-dependent presynaptic inhibition of GABAergic synaptic transmission, and thereby removes the inhibitory influence on LC neurons (disinhibition of the descending noradrenergic system) only under neuropathic pain states.
2. We addressed the therapeutic impact of increasing spinal glycine applied exogenously or via blockade of glycine transporter 1 (GlyT1) using its selective inhibitors sarcosine and NFPS on neuropathic and inflammatory pain in mice. Glycine, sarcosine and NFPS ameliorated thermal and mechanical hypersensitivity in Seltzer model mice, and reduced mechanical hypersensitivity in STZ injected diabetic mice. Moreover, they selectively inhibited the second phase of formalin evoked licking/biting behavior. In hippocampal slices prepared from Seltzer model mice, LTP was maintained at a significantly lower level than that in sham-treated mice. Such impairment of LTP was never observed when it was induced in the presence of NFPS. Together, an increase in endogenous glycine via GlyT1 blockade not only results in a net inhibitory influence on pain transmission at the spinal level but also supraspinally relieves decreased synaptic efficacy presumably related to cognitive disturbance often described inpatients with chronic pain.
3. In the pharmacological and physiological studies related with pain transmission between primary afferent fibers and superficial dorsal horn neurons, spinal cord slices with attached dorsal roots prepared from rats have been used. However, synaptic transmission using mice spinal cord slices attached dorsal roots is hardly evaluated. We adapted this rat spinal slice preparation to adult mice, and addressed whether HCN channels contribute to Aδ-and C-fiber-mediated EPSCs after peripheral nerve injury. Consistent with our behavioral study demonstrating that intrathecal injection of the HCN channel blocker ZD7288 reduced thermal and machanical hypersensitivity in Seltzer model mice, 7288 reduced Aδ-and C-fiber-mediated EPSCs. Less
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