Jian-Guo Cui

Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism.

&NA; Neuropathic pain may be effectively relieved by electric stimulation of the spinal cord (SCS). However, the underlying mechanisms for the ensuing pain relief are poorly understood. In a rat model of neuropathy displaying hypersensitivity to innocuous tactile stimuli, (allodynia), we have earlier demonstrated that SCS may normalise withdrawal response thresholds. In the present study, using microdialysis, it is shown that SCS induces a decreased release of the dorsal horn excitatory amino acids (EAA), glutamate and aspartate, concomitant with an increase of the GABA release. Local perfusion with a GABAB‐receptor antagonist in the dorsal horn transiently abolishes the SCS‐induced suppression of the EAA release. Thus, the effect of SCS on neuropathic pain and allodynia may be due to an activation of local GABAergic mechanisms inhibiting the EAA release which is chronically elevated in such conditions.

Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy

&NA; Peripheral hypersensitivity (hyperalgesia and allodynia) are common phenomena both in inflammatory and in neuropathic pain conditions. Several rat models of mononeuropathy (Bennett, Seltzer and Gazelius models) display such symptoms following partial injury to the sciatic nerve. Using immunohistochemistry and behavioral tests, we investigated inflammatory cell and cytokine responses in the sciatic nerve 14 days after injury created in these different models as well as after axotomy. Tactile hypersensitivity (‘allodynia’) was present in all Gazelius model rats whereas only 38 and 29% of the Bennett and Seltzer models, respectively, displayed this sign of neuropathy. The inflammatory reactions in rats with and without tactile allodynia were compared. Monocytes/macrophages (ED‐1), natural killer cells, T lymphocytes, and the pro‐inflammatory cytokines tumor necrosis factor‐&agr; (TNF‐&agr;) and interleukin‐6 (IL‐6), were significantly upregulated in all nerve injured rats in comparison to sham‐operated controls. Interestingly, ED‐1‐, TNF‐&agr;‐ and IL‐6‐positive cells increased more markedly in allodynic Bennett and Seltzer rats than in non‐allodynic ones. The magnitude of the inflammatory response does not seem to relate to the extent of damage to the nerve fibers because axotomized rats displayed much lower upregulation. Our findings indicate that the considerable increase in monocytes/macrophages induced by a nerve injury results in a very high release of IL‐6 and TNF‐&agr;. This may relate to the generation of tactile allodynia/hyperalgesia, since there was a clear correlation between the number of ED‐1 and IL‐6‐positive cells and the degree of allodynia. It is possible that measures to reduce monocyte/macrophage recruitment and the release of pro‐inflammatory interleukins after nerve damage could influence the development of neuropathic pain.

Release of gamma-aminobutyric acid in the dorsal horn and suppression of tactile allodynia by spinal cord stimulation in mononeuropathic rats.

OBJECTIVE The aim of the present study is to monitor the extracellular gamma-aminobutyric acid (GABA) levels in the lumbar dorsal horn of allodynic rats, which respond to spinal cord stimulation (SCS) with a normalization of the tactile withdrawal threshold. In addition, we monitored the GABA levels in nonresponding and sham-stimulated rats. METHODS Partial constriction injury of the sciatic nerve was performed, and a permanent electrode for SCS was inserted into the spinal canal. The response to SCS was assessed with von Frey hairs in awake animals. Later, microdialysis was performed in the dorsal horn of the spinal cord under halothane anesthesia. The concentration of GABA in the microdialysate was assessed by high-performance liquid chromatography. RESULTS Extracellular GABA levels in rats with sciatic nerve lesions and allodynia (2.3 +/- 0.5 nmol/L) were significantly lower (P < 0.001) than in control rats with intact sciatic nerves (8.1 +/- 1.0 nmol/L), whereas only slightly decreased GABA levels (5.7 +/- 1.1 nmol/L) were detected in nonallodynic rats with sciatic nerve lesions. In the allodynic rats, which respond to SCS by a normalization of the tactile withdrawal threshold, significantly (P < 0.001) increased GABA levels (6.7 +/- 2.3 nmol/L) were detected after SCS. In contrast, neither the allodynic rats, which did not respond to SCS, nor the sham-stimulated allodynic rats displayed increased GABA levels in response to stimulation. CONCLUSION Our results indicate that the development of allodynia, a common symptom in neuropathic pain states, may be linked to a decreased spinal release of GABA. We suggest that an SCS-induced release of GABA could be important for the suppression of allodynia observed in rats after SCS. Similar mechanisms could also be involved in the SCS-induced alleviation of pain in patients with peripheral neuropathy.

Effects of spinal cord stimulation on touch-evoked allodynia involve GABAergic mechanisms. An experimental study in the mononeuropathic rat

&NA; There is much evidence that tactile allodynia in rat models of mononeuropathy produced by sciatic nerve constriction is linked to disturbance of spinal GABAergic functions. Spinal cord stimulation (SCS) applied to such animals via chronically implanted electrodes may in some of the animals induce a significant increase of the withdrawal threshold in response to innocuous mechanical stimulation with von Frey filaments applied to the paw of the nerve ligated leg. The present study was performed in mononeuropathic animals with definite signs of tactile allodynia, which did Symbol respond to SCS. GABA and the GABAB‐agonist baclofen were administered intrathecally, in doses per se insufficient to influence the withdrawal thresholds, together with the previously ineffective SCS. This combination resulted in a marked and long‐lasting increase of the thresholds. The GABAA‐agonist muscimol given together with SCS also produced a similar, but less prominent threshold increase. The GABAB‐antagonist 5‐aminovaleric acid (5‐AVA) produced a transient suppression of the threshold increase induced by SCS together with either GABA or baclofen. In contrast, the GABAA‐antagonist bicuculline had no apparent inhibitory effect on the threshold augmentation produced by SCS combined with GABA or baclofen. It is concluded that SCS may operate by upgrading the spinal GABAergic systems and that its potential for producing pain relief is dependent upon the availability of responsive GABA‐containing inhibitory interneurons. Moreover, it seems that the effects of SCS are more linked to the GABAB‐ than to the GABAA‐receptor system. Symbol. No caption available.

Gabapentin and pregabalin suppress tactile allodynia and potentiate spinal cord stimulation in a model of neuropathy

Spinal cord stimulation (SCS) is an effective tool in alleviating neuropathic pain. However, a number of well‐selected patients fail to obtain satisfactory pain relief. Previous studies have demonstrated that i.t. baclofen and/or adenosine can enhance the SCS effect, but this combined therapy has been shown to be useful in less than half of the cases and more effective substances are therefore needed. The aim of this experimental study in rats was to examine whether gabapentin or pregabalin attenuates tactile allodynia following partial sciatic nerve injury and whether subeffective doses of these drugs can potentiate the effects of SCS in rats which do not respond to SCS. Mononeuropathy was produced by a photochemically induced ischaemic lesion of the sciatic nerve. Tactile withdrawal thresholds were assessed with von Frey filaments. Effects of increasing doses of gabapentin and pregabalin (i.t. and i.v.) on the withdrawal thresholds were analysed. These drugs were found to reduce tactile allodynia in a dose‐dependent manner. In SCS non‐responding rats, i.e. where stimulation per se failed to suppress allodynia, a combination of SCS and subeffective doses of the drugs markedly attenuated allodynia. In subsequent acute experiments, extracellular recordings from wide dynamic range neurones in the dorsal horn showed prominent hyperexcitability. The combination of SCS and gabapentin, at the same subeffective dose, clearly enhanced suppression of this hyperexcitability. In conclusion, electrical therapy and pharmacological therapy in neuropathic pain can, when they are inefficient individually, become effective when combined.

Photochemically induced ischaemic lesion of the rat sciatic nerve. A novel method providing high incidence of mononeuropathy

The incidence of behavioural signs of mononeuropathy in rats subjected to chronic constriction injury (CCI) of the sciatic nerve is unpredictable and often low. In the present study, an ischaemic lesion of the rat sciatic nerve was induced photochemically using a low power laser. In these rats tactile allodynia developed with a considerably greater incidence (95%) than in control rats subjected to CCI (45%). The allodynia lasted longer and was more prominent. Responses to thermal stimulation did not markedly differ between the two groups. The ischaemic lesions displayed marked degeneration, particularly of large myelinated fibres. The results suggest that laser irradiation of a peripheral nerve inducing a local photochemical reaction followed by Wallerian degeneration may be a convenient and reproducible experimental method of producing signs of peripheral mononeuropathy.

Spinal cord stimulation improves survival in ischemic skin flaps: an experimental study of the possible mediation by calcitonin gene-related peptide.

Currently, spinal cord stimulation is used to treat ischemia and ischemic pain, with the best results observed in vasospastic cases. It was earlier demonstrated that spinal cord stimulation may attenuate experimentally induced vasospasm in an island flap in the rat. The present study was designed to investigate whether preemptive spinal cord stimulation could increase long-term flap survival and to explore the neurohumoral mediation of the effect. A total of 56 rats were implanted with chronic spinal cord stimulation systems. Three days later, a groin flap based on the superficial epigastric vessels was harvested, and the single feeding artery was occluded by a detachable microvascular clip. After 12 hours, the clip was removed. Flap survival was evaluated after 7 days. Immediately before flap surgery, two groups of animals received 30 minutes of stimulation using current clinical parameters and with stimulation amplitudes of 70 (n = 10) or 90 percent (n = 8) of that evoking muscular contractions. The outcomes in these groups were compared with those in two control groups (n = 20; n = 10). In one group, an additional calcitonin gene-receptor peptide (CGRP) antagonist was intravenously injected before stimulation (n = 8). In the control groups without stimulation, virtually all flaps necrotized. In treated groups, flap survival was 60 percent at the lower intensity and almost 90 percent at the higher one. The administration of a CGRP antagonist before treatment reduced its efficacy to below 40 percent survival. The differences between the untreated and treated groups were significant. The decrease in survival after CGRP-receptor block was significant in one of two tests. Preemptive spinal cord stimulation increases survival of skin flaps with critical ischemia. The effects are dependent on the stimulation intensity and are possibly mediated by the release of CGRP in the periphery.

Neurotransmitter and Inflammatory Correlates in Experimental Neuropathy: Modulation by Electric Spinal Cord Stimulation

Neuropathic pain is often difficult to manage with pharmacotherapy but may be effectively relieved by electric stimulation of the spinal cord (SCS). This mode of treatment has been practised for more than three decades, but the knowledge about the mechanisms involved in the pain alleviating effect is still fragmentary. Injury of a peripheral nerve induces multiple pathological changes in the peripheral nerve itself, in the dorsal root ganglion (DRG) and in the dorsal horn (DH) of the spinal cord. It may further result in the development of neuropathic symptoms including, besides chronic pain, hypersensitivity to peripheral stimuli (allodynia, dysaesthesia and hyperalgesia).