Bengt Linderoth

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.

Physiology of Spinal Cord Stimulation: Review and Update

Spinal cord stimulation (SCS) was an outgrowth of the well‐known gate control theory presented by Melzack and Wall in 1965. Although the method has been used to treat chronic severe pain for more than three decades, very little was known about the physiological and biochemical mechanisms behind the beneficial effects until recently. We now know that SCS activates several different mechanisms to treat different types of pain such as neuropathic and ischemic. In general, these mechanisms seem most dependent on activation of only a few segments of the spinal cord. However, both animal studies and human observations have indicated that supraspinal circuits may contribute as well. In the treatment of neuropathic pain, intermittent SCS may give several hours of pain relief after cessation of the stimulation. This protracted effect indicates long‐lasting modulation of neural activity involving changes in the local transmitter systems in the dorsal horns. In ischemic pain, animal experiments demonstrate that inhibition of afferent activity in the spinothalamic tracts, long‐term suppression of sympathetic activity, and antidromic effects on peripheral reflex circuits may take part in the pain alleviation. Moderate SCS intensities seem to evoke sympathetic inhibition, but higher stimulation intensities may induce antidromically mediated release of vasoactive substances, eg, the calcitonin gene‐related peptide (CGRP), resulting in peripheral vasodilation. The anti‐ischemic effect of SCS in angina pectoris due to intermittent coronary ischemia probably occurs because application of SCS appears to result in a redistribution of cardiac blood supply, as well as a decrease in tissue oxygen demand. Recent studies indicate that SCS modulates the activity of cardiac intrinsic neurons thereby restricting the arrythmogenic consequences of intermittent local coronary ischemia. The present state of knowledge is briefly reviewed and recent research directions outlined.

Motor Cortex Stimulation as Treatment of Trigeminal Neuropathic Pain

A report is given on first experiences with motor cortex stimulation in 10 patients with different forms of neuropathic pain. Three of them had central pain as sequelae of cerebrovascular disease. In none of them did the stimulation provide pain relief. Two patients had pain from peripheral nerve injuries. One did not respond, but the other obtained about 50% pain relief. The remaining 5 patients with trigeminal neuropathy experienced definite pain relief varying between 60 and 90%. During test stimulation most patients had one or two short-lasting generalized seizures. But no one had any motor effects after permanent implantation. Motor cortex stimulation appears to be a new and promising possibility of pain treatment, especially in cases with trigeminal neuropathy, but many problems have yet to be solved, before a clear indication could be given.

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.

Modulation of intrinsic cardiac neurons by spinal cord stimulation : implications for its therapeutic use in angina pectoris

OBJECTIVE Electrical stimulation of the dorsal aspect of the upper thoracic spinal cord is used increasingly to treat patients with severe angina pectoris refractory to conventional therapeutic strategies. Clinical studies show that spinal cord stimulation (SCS) is a safe adjunct therapy for cardiac patients, producing anti-anginal as well as anti-ischemic effects. However, little information is yet available about the underlying mechanisms involved. METHODS In order to determine its mechanism of action, the effects of SCS on the final common integrator of cardiac function, the intrinsic cardiac nervous system, was studied during basal states as well as during transient (2 min) myocardial ischemia. Activity generated by intrinsic cardiac neurons was recorded in 9 anesthetized dogs in the absence and presence of myocardial ischemia before, during and after stimulating the dorsal T1-T2 segments of the spinal cord at 66 and 90% of motor threshold using epidural bipolar electrodes (50 Hz; 0.2 ms; parameters within the therapeutic range used in humans). RESULTS The SCS suppressed activity generated by intrinsic cardiac neurons. No concomitant change in monitored cardiovascular indices was detected. Neuronal activity increased during transient ventricular ischemia (46%), as well as during the early reperfusion period (68% compared to control). Despite that, activity was suppressed during both states by SCS. CONCLUSIONS SCS modifies the capacity of intrinsic cardiac neurons to generate activity. SCS also acts to suppress the excitatory effects that local myocardial ischemia exerts on such neurons. Since no significant changes in monitored cardiovascular indices were observed during SCS, it is concluded that modulation of the intrinsic cardiac nervous system might contribute to the therapeutic effects of SCS in patients with angina pectoris.

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.

Sympathetic mediation of peripheral vasodilation induced by spinal cord stimulation: animal studies of the role of cholinergic and adrenergic receptor subtypes.

Electric spinal cord stimulation (SCS) is widely used as a treatment modality for ischemic pain in peripheral arterial insufficiency. The background for the therapeutic effect may be a temporary inhibition of sympathetically maintained peripheral vasoconstriction. In this series of experiments, the involvement of different types of cholinergic and adrenergic receptor subclasses in the vasodilatory effect was explored in anesthetized rats. The microcirculation in hindlimb skin and hamstring muscle was studied by the laser Doppler technique. The ganglionic blocker hexamethonium as well as the nicotinic receptor antagonist chlorisondamine abolished the effect in both vascular beds, whereas the muscarinic receptor antagonists pirenzepine and atropine were ineffective. Among the adrenergic receptor active compounds, phentolamine, prazosine (an alpha 1-receptor antagonist), and clonidine in high doses suppressed the SCS-induced vasodilation. Yohimbine (an alpha 2-receptor antagonist) did not alter the effect. The beta-adrenergic compounds had a differential effect on muscle and skin perfusion. Atenolol, a beta 1-receptor antagonist, inhibited SCS-induced vasodilation only in the skin, whereas the beta 2-receptor antagonist butoxamine selectively depressed the muscle response. The vasodilatory effect of SCS in the animal model used here seems to a large extent to be mediated by an inhibitory effect on peripheral vasoconstriction maintained via efferent sympathetic activity involving nicotinic transmission in the ganglia and the postganglionic alpha 1-adrenoreceptors. The involvement of beta-receptors seems to be different in skin and muscle, beta 1 being more important for the changes in the skin and beta 2 being more important for those in muscle. The high-intensity antidromic response, earlier believed to explain how SCS exerted its vasodilatory effect, was resistant to cholinergic and adrenergic manipulations and seems to depend on entirely different mechanisms.

In vivo release of substance P in cat dorsal horn studied with microdialysis

Variations in the extracellular concentration of substance P (SP) were measured in cat dorsal horn in vivo by microdialysis and radioimmunoassay. Electrical unilateral stimulation of the sciatic nerve was used to evoke release of SP. At high-intensity stimulation, activating slowly conducting (approx. 0.9 m/s) fibres, there was an increase in substance P-like immunoreactivity (SP-LI) to 338% of the preceding control value (P less than 0.05, n = 5) in the dialysates collected at levels L6-L7 at the stimulated side. A less pronounced increase, to 164% of the basal level, was found at the contralateral side. More cranially (L1-L5) in the dorsal horn at the stimulated side, only a moderate or no increase in SP-LI was seen. Stimulation with low intensity, sufficient to activate fast (greater than 20 m/s), but not slowly conducting fibres, evoked no increase in SP-LI. The results indicate that unilateral peripheral C-fibre activation induces a local SP release in the dorsal horn present also on the side not stimulated.

Effects of sympathectomy on skin and muscle microcirculation during dorsal column stimulation: animal studies.

Electric stimulation of the dorsal spinal cord (DCS) in the treatment of pain in peripheral vascular disease is known to enhance peripheral circulation, but the mechanisms are still obscure. An earlier study has provided indirect evidence that the vasodilator effect is dependent upon alteration of sympathetic vasomotor activity. In the present study, surgical interruption of sympathetic pathways was performed to define the role of the sympathetic system for the stimulation-induced vasodilation. Three groups of normal rats were used: one group subjected to lumbar sympathectomy, one group sham-operated about 1 week before performing spinal cord stimulation, and a third group, without pretreatment, serving as a second control. Stimulation was applied to one dorsal column at the thoracolumbar junction, and peripheral microcirculation was recorded in hind limb skin and muscle by laser Doppler technique. The stimulation parameters were chosen to correspond with those used clinically in man. A cold test with monitoring of cold-induced changes in peripheral blood flow was used to assess the completeness of the sympathectomy. The preoperative cold test induced a reciprocal response, vasoconstriction in the skin and vasodilation in muscle. DCS with clinical parameters did not produce this reciprocity in the control and sham-operated rats, but induced a vasodilation in both skin and muscle. After complete sympathectomy, defined as postoperative disappearance of the vasomotor responses to cold, the vasodilation in skin and muscle in response to DCS was abolished; however, the vasodilatory response to high-intensity stimulation (approximately 10 times the motor threshold) was not affected. Incomplete sympathetic denervation in some animals resulted in partial preservation of a vasodilatory response to DCS.(ABSTRACT TRUNCATED AT 250 WORDS)