Neuronal hyperexcitability in the ventral posterior thalamus of neuropathic rats: modality selective effects of Pregabalin

Neuropathic pain represents a substantial clinical challenge; understanding the underlying neural mechanisms and back-translation of therapeutics could aid targeting of treatments more effectively. The ventral posterior thalamus (VP) is the major termination site for the spinothalamic tract and relays nociceptive activity to the somatosensory cortex, however under neuropathic conditions, it is unclear how hyperexcitability of spinal neurones converges onto thalamic relays. This study aimed to identify neural substrates of hypersensitivity, and the influence of pregabalin on central processing. In vivo electrophysiology was performed to record from VP wide dynamic range (WDR) and nociceptive-specific (NS) neurones in anaesthetised spinal nerve-ligated (SNL), sham-operated and naïve rats. In neuropathic rats, WDR neurones had elevated evoked responses to low and high intensity punctate mechanical stimuli, dynamic brushing, innocuous and noxious cooling, but less so to heat stimulation of the receptive field. NS neurones in SNL rats also displayed increased responses to noxious punctate mechanical stimulation, dynamic brushing, noxious cooling and noxious heat. Additionally, WDR, but not NS, neurones in SNL rats exhibited substantially higher rates of spontaneous firing, which may correlate with ongoing pain. The ratio of WDR:NS neurones was comparable between SNL and naïve/sham groups suggesting relatively few NS neurones gain sensitivity to low intensity stimuli leading to a 'WDR phenotype'. After neuropathy, the proportion of cold sensitive WDR and NS neurones increased, supporting that changes in frequency dependent firing and population coding underlie cold hypersensitivity. In SNL rats, pregabalin inhibited mechanical and heat responses but not cold evoked or elevated spontaneous activity