In the present study we confirm that peripheral nerve injury (CCI) results in long-distance changes in responsiveness to peripheral stimulation in third-order pain-processing neurons of the ventral posterolateral (VPL) nucleus of the thalamus that receive inputs from the injured contralateral sciatic nerve in animals that display lowered behavioral nociceptive thresholds [14, 18]. These changes include increased rates of firing in response to natural peripheral stimuli equivalent to light touch, pressing of the skin, and pinching of the skin. Our new data also document the abnormal expression of the Nav1.3 voltage-gated sodium channel transcripts in the VPL during this time of neuronal hyperresponsiveness and reduced nociceptive thresholds. We observed no changes in the expression of neuronal sodium channels Nav1.1, Nav1.2, or Nav1.6 in VPL neurons, although we can not rule out a contribution of other channels that could have an affect on firing thresholds [19, 20]. Our results demonstrate for the first time, that changes in sodium channel expression within the thalamus are associated with abnormal sensory processing and chronic neuropathic pain after CCI.
The abnormal expression of Nav1.3 in third-order neurons suggests a mechanism whereby injury to a peripheral nerve can propagate pathological molecular changes to sequentially-ordered upstream targets. Second-order dorsal horn nociceptive neurons receive input from the periphery via the dorsal root ganglia, and project rostrally to third-order neurons within a pain-signaling pathway, located within the ventrobasal complex of the thalamus. Most of these spinothalamic projections terminate in the VPL, and this pathway underlies most of the transmission of nociceptive information from the periphery to the brain . No changes in expression of Nav1.3 were observed in other thalamic nuclei, such as the intralaminar nuclei , which is important in processing affective components of pain. This could be related to the relatively few number of projections from the lumbar spinal cord, or low levels of Nav1.3 transcript upregulation after CCI. We have previously demonstrated that Nav1.3 contributes directly to hyperresponsiveness of second-order dorsal horn neurons after CCI , and that knock-down of Nav1.3 expression with intrathecally-delivered antisense oligonucleotides that selectively target Nav1.3 mRNA can reduce Nav1.3 expression in NK1R-positive dorsal horn nociceptive neurons, quiet hyperresponsive dorsal horn neurons, and return behavioral nociceptive thresholds to near-normal levels.
In this study, we document Nav1.3 misexpression in third-order neurons after nerve injury. The number of Nav1.3-expressing neurons is quite low, and may reflect the fact that only a subset of neurons receives pathological input from dorsal horn neurons rendered hyperresponsive by DRG efferents. Through FosB immunoreactivity, the number of neurons of the VPL that are responsive to noxious stimulation has been studied and is also low ; the number of Nav1.3-positive neurons in our study closely approximates this number.
The factors that drive expression of Nav1.3 in these neurons are not yet clear, and a number of possibilities exist. First, if we assume that Nav1.3 enables a neuron to fire at higher-than-normal frequencies, it is possible that VPL neurons are upregulating Nav1.3 in order to accommodate high-frequency information received from the spinal cord. As soon as 3 days after injury, ectopic and inappropriate discharges originate in the injured axons and their cell bodies within the DRG [1, 24–26]. This abnormal firing could drive dorsal horn neurons to relay higher frequency afferent information supraspinally towards the VPL, which in turn also become hyperresponsive in response to increased drive and upregulate Nav1.3 to accommodate higher than normal firing frequencies. Second, VPL neurons may undergo reactive changes that make them hyperresponsive. Abnormal firing has been shown to originate and persist within the dorsal horn after peripheral injury [3–5, 27], as well as the thalamus after spinal cord injury after interruption of spinal afferent barrage . Activity-dependent central sensitization can outlast the conditioning stimulus for hours . Third, while the up-regulated expression of Nav1.3 within DRG neurons following axotomy appears to be due in part to deprivation from peripheral pools of neurotrophic factors [29–31], the signals that trigger Nav1.3 upregulation within third-order neurons have not been identified. It is known that after peripheral nerve injury 2-deoxyglucose metabolic activity  and regional blood flow  are increased in the thalamus, and that changes in cannabinoid receptors  and monoamine release  occur, but whether these are linked to Nav1.3 expression is unclear.
Nav1.3 recovers from inactivation rapidly and produces a depolarizing response to small stimuli close to resting potential, and produces a persistent current – increasing the excitability of cells that express Nav1.3 [7, 10–12]. The Nav1.3 sodium channel has been linked to pain-related phenomena in a variety of model systems. Increased expression of Nav1.3 occurs in DRG and dorsal horn neurons following injury to the sciatic nerve [6, 7, 9, 36, 37], and while expression of Nav1.3 is not increased in axotomized cortical pyramidal neurons . Up-regulation of Nav1.3 expression in DRG neurons is associated with allodynia and hyperalgesia . Similarly, pain after spinal cord injury is ameliorated after knock-down of Nav1.3 [9, 17, 39].
Sodium channel blockade after peripheral  or central  injury with systemic lidocaine administration has been shown to be effective in the amelioration of chronic pain. It is not yet known how lidocaine, for example, might affect sodium channel dysregulation after experimental injury, but this is an important question to ask.