Significant decreases in the protein levels of potassium-chloride co-transporter 2 (KCC2) were detected in the ipsilateral spinal dorsal horn 4h following loose ligation of the sciatic nerve. These decreases were associated with a change in hindlimb weight distribution suggestive of pain behavior. In contrast, no changes in GABA-A receptor subunit alpha-1 levels were detected. The decreases in KCC2 coincided with a significant ipsilateral increase in BDNF protein levels. Both the decreases in KCC2 levels and the early pain behavior were prevented by intrathecal pre-treatment with the BDNF-sequestering TrkB/Fc chimera protein or the tyrosine kinase blocker K252a. The ligationassociated decreases in KCC2 levels were transient. In the ipsilateral spinal dorsal horn of ligated animals exhibiting weight-bearing pain behavior 7 days after the ligation the KCC2 levels were identical to those in control or sham-operated animals. These data suggested that TrkB-dependent reduction in KCC2 protein levels in the spinal dorsal horn was an early consequence of peripheral nerve injury. This decrease in KCC2 may have elicited an early increase in overall dorsal horn neuronal excitability perhaps through a loss of GABA inhibition which is critically dependent on KCC2 activity. The increased neuronal excitability may in turn have caused enhanced and exaggerated communication between primary afferents and dorsal horn neurons to contribute to the early behavioral signs of pain.

Plasticity in the spinal dorsal horn may underlie the development of chronic pain following peripheral nerve injury or inflammation. In this study, we examined whether chronic constriction injury of the sciatic nerve was associated with changes in the immunoreactive content of cyclic AMP response element binding protein (CREB), protein kinase A (PKA), and calcineurin Aalpha and Abeta in the spinal dorsal horn. In animals exhibiting thermal hyperalgesia as a behavioral sign of neuropathic pain 7 days after loose ligation of the sciatic nerve (chronic constriction injury), there was a significant increase in the content of phosphorylated (activated) CREB (pCREB). In contrast, following the typical disappearance of thermal hyperalgesia 28 days after loose ligation surgery, there were no differences in pCREB content between control and sciatic ligation animals. The increased CREB activation associated with thermal hyperalgesia was accompanied by significant decreases in the content of both calcineurin Aalpha and Abeta. In contrast, there were no differences in the content of non-phosphorylated CREB, and phosphorylated or non-phosphorylated PKA between control and sciatic ligation animals either 7 or 28 days after surgery. These data established a close association in the expression of thermal hyperalgesia with CREB activation and decreased calcineurin content in the spinal dorsal horn. The data revealed a significant but reversible shift in the manner in which spinal neurons processed sensory information following peripheral nerve injury, and lent further support to the notion that plasticity in the spinal dorsal horn may have contributed to the development of chronic pain.

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We examined whether continual constant-rate infusion of lidocaine would provide analgesia during the initial post-injury phase in the chronic constriction injury model of neuropathic pain. Male Sprague-Dawley rats were divided into control and ligated groups and infused with saline or lidocaine (0.15, 0.33, 0.67, and 1.3mg/kg/h) via subcutaneously implanted Alzet((R)) osmotic minipumps. Thermal withdrawal latencies were obtained prior (Day 0) and 3 days after loose sciatic ligation and pump implantation surgery. Ligated animals receiving lidocaine at 0.67 or 1.3mg/kg/h exhibited no change in withdrawal latency on Day 3 after surgery, indicating that lidocaine at these doses prevented the development of thermal hyperalgesia as a sign of neuropathic pain. In contrast, ligated animals treated with saline or lidocaine at 0.15 or 0.33mg/kg/h exhibited hyperalgesia on Day 3 after surgery, indicating that these lower doses of lidocaine failed to provide analgesia. Control animals treated with saline or any of the lidocaine doses exhibited no change in withdrawal latencies between Day 0 and Day 3. In a separate group of ligated animals, lidocaine infusion (0.67mg/kg/h) that was started 24h after sciatic ligation surgery reversed the already present thermal hyperalgesia. Average plasma lidocaine concentrations were 0.11, 0.36, and 0.45microg/ml for animals receiving 0.33, 0.67 and 1.3mg/kg/h of lidocaine, respectively. These results suggest that continual systemic infusion of lidocaine prevents or reverses the development of neuropathic pain following chronic constriction injury. These results add to the increasing body of evidence supporting the therapeutic value of preemptive and post-operative lidocaine administration for the relief of neuropathic pain.

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