Activation of voltage-dependent calcium channels (VDCC) is critical for neurotransmitter release. Calcium ion channels have also been shown to influence the generation of hypersensitivity and in particular, a role for N-type Ca21 channels has been shown. N-type, but not P- or Q-type, Ca21 channel antagonists can attenuate hyper-sensitivity to mechanical and heat stimuli in models of neuropathic pain.71,72 Furthermore, cannabinoid receptor agonists, known to have analgesic effect in nerve injury models, attenuate Ca21 flux at N-type channels.
A calcium channel subunit that has received much attention of late is the a28-1 subunit. This subunit is up-regulated in rat DRG neurons, on central afferents terminals and on neurons within the spinal dorsal horn following nerve injury (Figure 1.5).7475 This is correlated with pain behavior following peripheral nerve injury suggesting that a28-1 may contribute to neuroplasticity in neuropathic pain. In support of this, transgenic mice that constitutively overexpress a28-1 in neuronal tissues demonstrate pain behavior and exaggerated and prolonged dorsal horn neuronal responses to peripheral mechanical and thermal stimulation.76 Furthermore, the a28-1 subunit is thought to be the site of action of gabapentin77, 78 and pregabalin,79 which are effective in relieving signs of hypersensitivity in animal models80 and neuropathic pain in man.64,81
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