The effect of spinal cord stimulation frequency in experimental painful diabetic polyneuropathy.

BACKGROUND: Spinal cord stimulation (SCS) has been shown to be an effective treatment for painful diabetic polyneuropathy (PDP). An increase of efficacy is needed since only 67% of patients benefit from SCS. This study aimed to develop an animal model for SCS in PDP and study the effect of various stimulation frequencies on the functional outcome. As the pathophysiology of PDP is complex, including vasoconstriction and nerve injury, the frequency of SCS may result in different outcomes. METHODS: Diabetes mellitus was induced by an intraperitoneal injection of streptozotocin in 8-week-old female Sprague-Dawley rats (n=76; glucose >15 mmol/L; n=51). A SCS device was implanted at level Th13 4 weeks later. SCS of the dorsal columns was applied for 30 min and the effect on mechanical hypersensitivity was evaluated. RESULTS: Mechanical hypersensitivity developed in 26 rats, which were included (low-frequency, n=6; mid-frequency, n=8; high frequency, n=9; and sham, n=3). SCS of the dorsal columns was applied for 40 min, and the effect on mechanical hypersensitivity was evaluated. In all treatment groups, SCS resulted in reversal of mechanical hypersensitivity and a clinically relevant reduction was achieved in 70% of animals. No differences in efficacy were found between the different treatment groups. CONCLUSIONS: The pain-relieving effect of SCS in PDP was studied in an experimental model. Our study shows that SCS on mechanical hypersensitivity in PDP rats is equally effective when applied at low, mid and high frequency.

Decreased intracellular GABA levels contribute to spinal cord stimulation-induced analgesia in rats suffering from painful peripheral neuropathy: the role of KCC2 and GABA(A) receptor-mediated inhibition.

Elevated spinal extracellular γ-aminobutyric acid (GABA) levels have been described during spinal cord stimulation (SCS)-induced analgesia in experimental chronic peripheral neuropathy. Interestingly, these increased GABA levels strongly exceeded the time frame of SCS-induced analgesia. In line with the former, pharmacologically-enhanced extracellular GABA levels by GABA(B) receptor agonists in combination with SCS in non-responders to SCS solely could convert these non-responders into responders. However, similar treatment with GABA(A) receptor agonists and SCS is known to be less efficient. Since K⁺ Cl⁻ cotransporter 2 (KCC2) functionality strongly determines proper GABA(A) receptor-mediated inhibition, both decreased numbers of GABA(A) receptors as well as reduced KCC2 protein expression might play a pivotal role in this loss of GABA(A) receptor-mediated inhibition in non-responders. Here, we explored the mechanisms underlying both changes in extracellular GABA levels and impaired GABA(A) receptor-mediated inhibition after 30 min of SCS in rats suffering from partial sciatic nerve ligation (PSNL). Immediately after cessation of SCS, a decreased spinal intracellular dorsal horn GABA-immunoreactivity was observed in responders when compared to non-responders or sham SCS rats. One hour later however, GABA-immunoreactivity was already increased to similar levels as those observed in non-responder or sham SCS rats. These changes did not coincide with alterations in the number of GABA-immunoreactive cells. C-Fos/GABA double-fluorescence clearly confirmed a SCS-induced activation of GABA-immunoreactive cells in responders immediately after SCS. Differences in spinal dorsal horn GABA(A) receptor-immunoreactivity and KCC2 protein levels were absent between all SCS groups. However, KCC2 protein levels were significantly decreased compared to sham PSNL animals. In conclusion, reduced intracellular GABA levels are only present during the time frame of SCS in responders and strongly point to a SCS-mediated on/off GABAergic release mechanism. Furthermore, a KCC2-dependent impaired GABA(A) receptor-mediated inhibition seems to be present both in responders and non-responders to SCS due to similar KCC2 and GABA(A) receptor levels.

Successful pain relief in non-responders to spinal cord stimulation: the combined use of ketamine and spinal cord stimulation.

Although spinal cord stimulation (SCS) is an established therapy for chronic neuropathic pain, still 30% of patients do not respond adequately to trial stimulation. These so called "non-responders" do not receive a permanent implantation for pain relief. The induction and maintenance of central sensitization plays a pivotal role in (chronic) neuropathic pain and is thought to be the resultant of the activation of the N-methyl-d-aspartate (NMDA) receptor in the dorsal horn. Blocking the NMDA receptor through the use of the non-competitive blocker ketamine has shown to attenuate neuropathic pain, although the undesirable side effects limit its use. The present study was performed to examine whether the combination of SCS with an individually determined sub-effective dose of intrathecal (i.t.) ketamine could convert non-responders into responders in rats with chronic neuropathic pain. Rats received a partial ligation of the sciatic nerve for the induction of neuropathic pain. Animals with tactile hypersensitivity to von Frey monofilaments (n=15) received 30 min of SCS. Non-responders to SCS (n=8) received their individually determined sub-effective i.t. dose of ketamine followed by 30 min of SCS. No side effects of the sub-effective dose of ketamine could be noted. The combined treatment of SCS and sub-effective dose of i.t. ketamine in non-responders resulted in a significant reduction of the withdrawal threshold in all previous non-responders to SCS, thereby converting them into responders to SCS.

Differential GABAergic disinhibition during the development of painful peripheral neuropathy.

An impaired spinal GABAergic inhibitory function is known to be pivotal in neuropathic pain (NPP). At present, data concerning time-dependent alterations within the GABAergic system itself and post-synaptic GABA(A) receptor-mediated inhibitory transmission are highly controversial, likely related to the experimental NPP model used. Furthermore, it is unknown whether the severity of NPP is determined by the degree of these GABAergic disturbances. In the present study we therefore examined in one experimental animal model whether anatomical changes within the spinal GABAergic system and its GABA(A) receptor-mediated inhibitory function are gradually aggravated during the development of partial sciatic nerve injury (PSNL)-induced NPP and are related to the severity of PSNL-induced hypersensitivity. Three and 16 days after a unilateral PSNL (early and late NPP, respectively), GABA-immunoreactivity (GABA-IR) and the number of GABA-IR neuronal profiles were determined in Rexed laminae 1-3 of lumbar spinal cord cryosections. Additionally, the efficiency of dorsal horn GABA(A) receptor-induced inhibition was examined by cation chloride cotransporter 2 (KCC2) immunoblotting. NPP-induced hypersensitivity was only observed at the ipsilateral side, both at early and late time points. During early NPP, a decrease in ipsilateral dorsal horn GABA-IR was observed without alterations in the number of GABA-IR neuronal profiles or KCC2 protein levels. In contrast, bilateral increases in spinal GABA-IR accompanied by an unchanged number of GABA-IR interneurons were observed during late NPP. This was furthermore attended with decreased ipsilateral KCC2 levels. Moreover, the degree of hypersensitivity was not related to disturbances within the spinal GABAergic system at all time points examined. In conclusion, our anatomical data suggest that a dysfunctional GABA production is likely to be involved in early NPP whereas late NPP is characterized by a combined dysfunctional GABA release and decreased KCC2 levels, the latter suggesting an impaired GABA(A) receptor-mediated inhibition.