High-frequency spinal cord stimulation treatment attenuates the increase in spinal glutamate release and spinal miniature excitatory postsynaptic currents in rats with spared nerve injury-induced neuropathic pain.

High-frequency spinal cord stimulation (HFSCS) at 10 kHz provides paresthesia-free treatment for chronic pain. However, the underlying mechanisms of its action have not been fully elucidated. The aim of the present study was to investigate the effect of HFSCS treatment on spinal glutamate release and uptake in spared nerve injury (SNI) rats. HFSCS was applied to the T10/T11 spinal cord 3 days after SNI. The concentration of spinal glutamate, glutamate transporter activity and miniature excitatory postsynaptic currents (mEPSCs) from neurons in lamina II were evaluated. HFSCS treatment alleviated SNI pain induced by mechanical and cold allodynia. HFSCS treatment also partially restored altered spinal glutamate uptake activity, the levels of spinal glutamate, and the frequency of mEPSCs following SNI. In conclusion, HFSCS treatment attenuated SNI-induced neuropathic pain and partially restored the altered glutamate uptake after SNI.

Early high-frequency spinal cord stimulation treatment inhibited the activation of spinal mitogen-activated protein kinases and ameliorated spared nerve injury-induced neuropathic pain in rats.

BACKGROUND: Neuromodulation therapies offer a treatment option that has minimal side effects and is relatively safe and potentially reversible. Spinal cord stimulation (SCS) has been used to treat various pain conditions for many decades. High-frequency SCS (HFSCS) involves the application of a single waveform at 10,000 Hz at a subthreshold level, therefore providing pain relief without any paresthesia. METHODS: We tested whether early HFSCS treatment attenuated spared nerve injury (SNI)-induced neuropathic pain. The phosphorylation profile of mitogen-activated protein kinases (MAPKs), i.e., extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38, was evaluated to elucidate the potential underlying mechanism. RESULTS: SNI of rat unilateral sciatic nerves induced mechanical hyperalgesia in the ipsilateral hind paws. Rats were assigned to SCS sessions with HFSCS (frequency 10 kHz; pulse width 30 µs; pulse shape of charge-balanced, current controlled; delivered continuously for 72 h), or sham stimulation immediately after SNI. Tissue samples were examined at 1, 3, 7, and 14 days after SNI. Behavioral studies showed that HFSCS applied to the T10/T11 spinal cord significantly attenuated SNI-induced mechanical hyperalgesia compared with the sham stimulation group. Moreover, western blotting revealed a significant attenuation of the activation of ERK1, ERK2, JNK1, and p38 in the dorsal root ganglia and the spinal dorsal horn. CONCLUSION: Application of HFSCS provides an effective treatment for SNI-induced persistent mechanical hyperalgesia by attenuating ERK, JNK, and p38 activation in the dorsal root ganglia and the spinal dorsal horn.

Pulsed Radiofrequency Attenuates Complete Freund's Adjuvant-Induced Epigenetic Suppression of Potassium Chloride Cotransporter 2 Expression.

Background: Pulsed radiofrequency (PRF) treatment offers pain relief for patients suffering from chronic pain who do not respond well to conventional treatments. We tested whether PRF treatment attenuated complete Freund's adjuvant (CFA)-induced inflammatory pain. Epigenetic modification of potassium-chloride cotransporter 2 (KCC2) gene expression was examined to elucidate the potential contributing mechanism. Methods: Male Sprague-Dawley rats were injected with CFA into the plantar surface of the left hind paw to induce inflammation. PRF (20 minutes of 500-kHz RF pulses, delivered at a rate of 2 Hz, maximum temperature 42ºC) was delivered to the L5 and L6 anterior primary ramus just distal to the intervertebral foramen of adult CFA or saline rats. The hind paw withdrawal threshold to von Frey filament stimuli and withdrawal latency to radiant heat were determined before and after CFA. Acetyl-histone H3 and H4 was determined by chromatin immunoprecipitation in spinal dorsal horn. KCC2 expression was determined by Western blot. Inhibitory synaptic function was evaluated by patch clamp in lamina II neurons. Results: KCC2 gene expression was suppressed through histone hypoacetylation, resulting in decreased efficacy of GABAergic signaling in CFA rats. PRF increased histone acetylation and KCC2 expression, partially restored the GABA synaptic function, and relieved sensitized pain behavior. Conclusion: These findings suggest that PRF might be an alternative therapy for inflammatory pain. One of the underlying mechanisms is through modification of KCC2, which is an important determinant for the efficacy of inhibitory neurotransmission in the spinal cord, and its expression levels are regulated by histone acetylation epigenetically following inflammation.

Reduction of spinal glycine receptor-mediated miniature inhibitory postsynaptic currents in streptozotocin-induced diabetic neuropathic pain.

Diabetic neuropathic pain (DNP) is a common clinical problem, and the mechanisms underlying the onset and progression of this complication are poorly understood. The present study examined the glycine receptors (GlyR) in the control of synaptic input to dorsal horn neurons in diabetes. Male Sprague-Dawley rats with or without streptozotocin (STZ) intraperitoneal injections were used. Tactile sensitivities were assessed by measuring paw withdrawal thresholds to von Frey filaments for four weeks. The extent of GlyR-mediated inhibition controlling primary afferent-evoked excitation in dorsal horn neurons was examined by using the whole cell patch clamp recording technique in isolated adult rat spinal cord slices. The content of the spinal dorsal horn glycine levels was measured by microdialysis. An intrathecal glycine agonist injection was used to test whether mimicking endogenous glycine-receptor-mediated inhibition reduces DNP. We found that persistent hyperglycemia induced by the administration of STZ caused a decrease in the paw withdrawal latency to mechanical stimuli. The miniature inhibitory post-synaptic current (mIPSC) rise, decay kinetics and mean GlyR-mediated mIPSC amplitude were not affected in DNP. The mean frequency of GlyR-mediated mIPSC of lamina I neurons from DNP rats was, however, significantly reduced when compared with neurons from control rats. Principal passive and active membrane properties and the firing patterns of spinal lamina I neurons were not changed in DNP rats. Spinal microdialysis rats had a significantly decreased glycine level following its initial elevation. The intrathecal administration of glycine diminished tactile pain hypersensitivity in DNP rats. In conclusion, these results indicate that long-lasting hyperglycemia induced by STZ injections leads to a reduced glycinergic inhibitory control of spinal lamina I neurons through a presynaptic mechanism.

Altered mitochondrial ATP synthase expression in the rat dorsal root ganglion after sciatic nerve injury and analgesic effects of intrathecal ATP.

Mitochondrial ATP synthase has multiple interdependent biological functions in neurons. Among them, ATP generation and regulation are the most important. The present study investigated whether the expression of mitochondrial ATP synthase correlates with symptoms of neuropathic pain in adult rats after axotomy, and whether intrathecal ATP administration is therapeutic in these neuropathic rats. Male Sprague-Dawley rats received left sciatic nerve transection (axotomy) and were randomly designated to a control (sham-operated) group, a neuropathic pain group (axotomy), a neuropathic pain and intrathecal sterile saline group, and a neuropathic pain and intrathecal ATP group. The thermal and mechanical sensitivity tests were performed at 1, 3, 5, and 7 days after axotomy. Left L4-L5 dorsal root ganglions (DRGs) were harvested to assess mitochondrial ATP synthase by immunoblotting and immunohistochemistry. After nerve injury, the expression of mitochondrial ATP synthase was decreased in protein extracts and was found mainly in C-fiber and A-δ fiber neurons of the DRGs. The decreased expression of mitochondrial ATP synthase and its subcellular localization were related to thermal and mechanical hyperalgesia. Administration of intrathecal ATP significantly attenuated thermal and mechanical hypersensitivity throughout the experimental period, which suggests its potential role in the treatment of neuropathic pain.

Two cases of massive pleural effusion noted only after induction of anesthesia in living donor liver transplantation.

Two adult patients who underwent living donor liver transplantation with acute accumulation of right-side pleural effusion are reported. The chest X-ray of patient 1 showed no specific finding 3 days before the operation, and patient 2 was known to have pleural effusion and underwent pigtail drainage before transplant. After anesthesia induction and insertion of central venous catheters, a portable chest radiograph was taken to confirm the positions of the central venous catheters and endotracheal tube. A massive right-side pleural effusion was noted unexpectedly in both patients. Approximately 2,000 ml transudative fluid was surgically drained through the right diaphragm in patient 1 upon opening of the abdominal cavity. The acute accumulation of massive pleural fluid in patient 2 was caused by clamping of the pigtail drainage tube during patient transfer to the operating room; upon unclamping of the tube, 2,000 ml fluid was drained. The intraoperative and postoperative transplant courses of both patients were uneventful. Both were discharged from the hospital in stable condition. Our cases suggest that chest X-ray after induction of the anesthesia and before liver transplantation surgery is recommended. In addition to documenting the positions of the central venous catheters and endotracheal tube, a potential life-threatening pleural effusion requiring appropriate management may be detected.

Use of spectral entropy monitoring in reducing the quantity of sevoflurane as sole inhalational anesthetic and in decreasing the need for antihypertensive drugs in total knee replacement surgery.

BACKGROUND: The use of spectral entropy for monitoring the depth of anesthesia or level of hypnosis in surgery or painful procedures can reduce the consumption of drugs and shorten the recovery time of total intravenous anesthesia such as by propofol. The aim of this study was to investigate: (1) the consumption of sevoflurane as the sole anesthetic; and (2) hemodynamic stability in orthopedic surgery with tourniquet inflation under the guidance of spectral entropy, in contrast with the conventional method. METHODS: Sixty-five patients, ASA I or II, scheduled to undergo total knee replacement were enrolled and randomized into an entropy-guided group or a conventionally-monitored group. In the conventional group, the depth of anesthesia was judged by the clinical experience of the anesthesia provider based on the hemodynamic response. In the entropy group, state entropy (SE) and response entropy (RE) were kept within the range of 35-45 and an adequate gradient of 5-10 intraoperatively. The overall consumption of sevoflurane (mL) was monitored by the GE Datex-Ohemda S/5 Anesthetic Delivery Unit System. The physiologic changes during five major events in sequence in total knee replacement surgery, i.e., intubation, tourniquet inflation, skin incision, deflation and extubation, were observed closely over the first 5 minutes after each individual event. Within the first 5 minutes of each event, antihypertensive drugs were prohibited. The rest of the time, changes were recorded at 5-minute intervals and the use of rescue medication was allowed in case of need. We compared the heart rate, mean arterial pressure, SE, RE, sevoflurane concentration and rescue drugs in both groups. RESULTS: The sevoflurane consumption was significantly lower in the entropy group than in the conventional group (27.79 +/- 7.4 mL vs. 31.42 +/- 6.9 mL; p < 0.05). During the first 5 minutes of each major event, there were no significant differences in hemodynamics between the two groups. In the ensuing time, entropy-guided anesthesia was associated with significantly less frequent need of antihypertensive drugs (0.94 vs. 1.48 times; p = 0.043), especially in the 45-60 minutes after tourniquet inflation (p = 0.012). CONCLUSION: Using spectral entropy monitoring for guiding the depth of sevoflurane anesthesia in total knee replacement surgery can reduce its consumption and the frequency of use of antihypertensive drugs.