No abstract

These findings contribute to evidence identifying the σ(1) receptor as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and suggest σ(1) receptor antagonists as potential novel treatments for neuropathic pain.

Dorsal horn neurons in the young rat spinal cord-hindlimb preparation were physiologically classified as wide dynamic range (WDR), nociceptive specific (NS) or low threshold (LT) according to their excitatory responses to low and high intensity mechanical stimuli applied to the hindlimb skin. Two additional types were classified: neurons displaying only sub-threshold excitations (SUB) and neurons displaying inhibitory events (INH), such as inhibitory post-synaptic potentials or interruption of spontaneous spiking following cutaneous stimulation. Direct intracellular current injection revealed four different patterns of spiking behaviour: group A neurons were characterized by tonic firing in response to depolarizing current pulses; group B neurons were strongly phasic, producing only one spike at the beginning of the pulse; group A-B neurons generated an early unsustained (< 300 ms) burst of spikes; and group C neurons exhibited anomalous rectification in response to hyperpolarizing current which was followed by a voltage-dependent rebound excitation. A statistically significant (P < or = 0.01) association existed between a neuron's physiological classification and its electrophysiological profile. The majority of WDR neurons responded with tonic firing and were assigned to group A, while NS neurons were strongly represented in group A-B. All INH neurons were assigned to group C. LT neurons were distributed between groups A and A-B, and SUB neurons were distributed between groups A and B. These data indicate, firstly, that dorsal horn neurons possess heterogeneous membrane properties and, secondly, that a relationship exists between a neuron's biophysical profile and its excitatory or inhibitory response to peripheral cutaneous afferent stimulation. The implications for dorsal horn somatosensory processing are discussed.

Spinal administration of GABA A receptor modulators, such as the benzodiazepine drug diazepam, partially alleviates neuropathic hypersensitivity that manifests as spontaneous pain, allodynia, and hyperalgesia. However, benzodiazepines are hindered by sedative impairments and other side effect issues occurring mainly as a consequence of binding to GABA A receptors containing the ␣ 1 subunit. Here, we report on the novel subtype-selective GABA A receptor-positive modulator NS11394 [3Ј-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], which possesses a functional efficacy selectivity profile of ␣ 5 Ͼ ␣ 3 Ͼ ␣ 2 Ͼ ␣ 1 at GABA A ␣ subunit-containing receptors.

The M-current has been proposed as a potential target for analgesia under neuropathic pain conditions. M-currents and/or their molecular correlates, KCNQ proteins, have been demonstrated in key elements of the nociceptive system including spinal and dorsal root ganglion neurons. Here we demonstrate that retigabine, a selective KCNQ channel opener, applied at neuromatose endings modulates the excitability of axotomized fibres inhibiting ectopic discharges. Responses to mechanical and chemical stimulation were obtained from intact and previously axotomized Adelta- and C-fibres using in vitro preparations and extracellular electrophysiological recording techniques. Application of retigabine (10 microM) produced an estimated approximately 80% reduction in the number of discharges produced by mechanical and chemical stimulation of most axotomized fibres tested (24/27). The electrical threshold of stimuli applied to the neuroma was found to increase in the presence of retigabine (+17.5+/-2.3%) and to decrease in the presence of a high potassium medium (-16.5+/-3.7%). This indicates that retigabine produces a hyperpolarization and a subsequent reduction of the excitability in aberrant sensory endings. Application of XE-991 (10 microM), a KCNQ channel blocker, had no effect on responses to stimulation of the neuroma but blocked the effects of retigabine indicating a specific involvement of KCNQ channels. In contrast to the strong effects on ectopic discharges, retigabine did not change responses to stimulation recorded from intact receptors. Results indicate that KCNQ channel opening at axotomized endings may constitute a novel and selective mechanism for modulation of some neuropathic pain symptoms.