The antihypersensitivity actions of
gabapentin and
pregabalin have been well characterized in a large number of studies, although the underlying mechanisms have yet to be defined. We have been focusing on the supraspinal structure as a possible site for their action and have demonstrated that intracerebroventricular (i.c.v.) administration of
gabapentin and
pregabalin indeed decreases thermal and mechanical
hypersensitivity in a murine
chronic pain model involving partial
ligation of the sciatic nerve. This novel supraspinally mediated
analgesic effect was markedly suppressed by either depletion of central
noradrenaline (NA) or blockade of spinal alpha(2)-adrenergic receptors. Moreover, i.c.v. injection of
gabapentin and
pregabalin increased spinal NA turnover in mice only after
peripheral nerve injury. In locus coeruleus (LC) neurons in brainstem slices prepared from mice after
peripheral nerve injury,
gabapentin reduced the
gamma-aminobutyric acid (
GABA) type A receptor-mediated inhibitory postsynaptic currents (IPSCs).
Glutamate-mediated excitatory synaptic transmission was hardly affected. Moreover,
gabapentin did not reduce IPSCs in slices taken from mice given a
sham operation. Although
gabapentin altered neither the amplitude nor the frequency of miniature IPSCs, it reduced IPSCs together with an increase in the paired-pulse ratio, suggesting that
gabapentin acts on the presynaptic GABAergic nerve terminals in the LC. Together, the data suggest that
gabapentin presynaptically reduces GABAergic synaptic transmission, thereby removing the inhibitory influence on LC neurons only in
neuropathic pain states, leading to activation of the descending noradrenergic system.