Therapy using implanted organic bioelectronics.

Many drugs provide their therapeutic action only at specific sites in the body, but are administered in ways that cause the drug's spread throughout the organism. This can lead to serious side effects. Local delivery from an implanted device may avoid these issues, especially if the delivery rate can be tuned according to the need of the patient. We turned to electronically and ionically conducting polymers to design a device that could be implanted and used for local electrically controlled delivery of therapeutics. The conducting polymers in our device allow electronic pulses to be transduced into biological signals, in the form of ionic and molecular fluxes, which provide a way of interfacing biology with electronics. Devices based on conducting polymers and polyelectrolytes have been demonstrated in controlled substance delivery to neural tissue, biosensing, and neural recording and stimulation. While providing proof of principle of bioelectronic integration, such demonstrations have been performed in vitro or in anesthetized animals. Here, we demonstrate the efficacy of an implantable organic electronic delivery device for the treatment of neuropathic pain in an animal model. Devices were implanted onto the spinal cord of rats, and 2 days after implantation, local delivery of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) was initiated. Highly localized delivery resulted in a significant decrease in pain response with low dosage and no observable side effects. This demonstration of organic bioelectronics-based therapy in awake animals illustrates a viable alternative to existing pain treatments, paving the way for future implantable bioelectronic therapeutics.

High-Frequency (1 kHz) Spinal Cord Stimulation-Is Pulse Shape Crucial for the Efficacy? A Pilot Study.

OBJECTIVES: Conflicting data regarding the efficacy of high-frequency spinal cord stimulation (HF SCS) has prompted the issue of the possible importance of the shape of the stimulating pulses. The aim of this pilot study was to compare HF SCS applied with monophasic and biphasic pulses of two different durations with conventional SCS in a rat model of neuropathic pain. MATERIALS AND METHODS: Rats were operated with lesions of sciatic nerve branches according to the spared nerve injury procedure (SNI). Animals, which developed pathological tactile hypersensitivity after surgery, were implanted with four-polar miniature SCS leads. SCS was applied during 60 min with either conventional current parameters (monophasic pulse width [PW]: 200 µsec; 50 Hz and amplitude 80% of the motor threshold [MT]), or with high-frequency SCS (1 kHz) with monophasic or biphasic pulses, the latter with pulse widths of either 24 (12 + 12) or 48 (24 + 24) µsec. The outcomes were examined regarding change of tactile hypersensitivity during the one-hour SCS period and with two tests of thermal sensitivity. RESULTS: Conventional monophasic SCS, as well as HF SCS applied with monophasic PW = 24 µsec or with biphasic PW = 48 (24 + 24) µsec, had similar suppressive effects on tactile hypersensitivity. Solely, HF SCS applied with biphasic pulses with a total PW of 24 (12 + 12) µsec demonstrated no effect. Thermal hypersensitivity was unaffected by HF SCS with all pulse varieties. CONCLUSIONS: There is no significant difference in efficacy between HF SCS applied with low amplitude ("subparesthetic") monophasic and biphasic pulses. However, short PWs providing only 12 µsec of cathodal stimulation was ineffective, presumably because of insufficient electric charge transfer from the lead contacts to the nervous tissue.

Efficacy of kilohertz-frequency and conventional spinal cord stimulation in rat models of different pain conditions.

OBJECTIVES: The aim was to compare the effects of high-frequency spinal cord stimulation (HF-SCS) at subparesthetic intensity with conventional SCS in rat models of different types of pain. In addition, microrecordings of afferent activity in the dorsal columns during both types of SCS were performed to elucidate their mode of action. MATERIALS AND METHODS: Miniature SCS electrodes were implanted in all rats. One group was submitted to the spared nerve injury procedure (SNI) and another to inflammatory pain after carrageenan injection into a hind paw. All animals were tested for hypersensitivity to normally innocuous tactile and thermal stimuli. One group of normal healthy rats was submitted to acute nociceptive (pinch, heat) pain. Microrecording of afferent activity in the gracile nucleus (GN) was performed in a group of nerve-lesioned rats responding to conventional SCS. RESULTS: HF-SCS at 500, 1,000, or 10,000 Hz at subparesthetic amplitudes produced similar reductions in hypersensitivity due to nerve lesion as did conventional SCS at 50 Hz. HF-SCS showed no effect on thermal pain. A trial to rescue non-responders to conventional SCS using HF-SCS was not successful. There were no effects either of conventional or of HF-SCS on acute or inflammatory pain. Conventional SCS produced massive activation in the GN but no activation during HF-SCS, though normal peripherally evoked afferent activity remained. CONCLUSIONS: Conventional SCS proved equally effective to HF-SCS in various pain models. As no activity is conveyed rostrally in subparesthetic HF-SCS, we hypothesize that its mechanisms of action are primarily segmental.

Spinal GABAergic mechanisms in the effects of spinal cord stimulation in a rodent model of neuropathic pain: is GABA synthesis involved?

OBJECTIVES: The effects of spinal cord stimulation (SCS) on the spinal γ-amino butyric acid (GABA) system have previously been studied in animal models of neuropathic pain. These studies, confirming the pivotal role of segmental GABA actions for the efficacy of SCS, have led to the question if the disturbance of the GABA inhibitory system as demonstrated both in basal and clinical studies also encompasses malfunction of the GABA synthesis. METHODS: Rat models of neuropathic pain were submitted to SCS applied with "clinical SCS parameters." The levels of the GABA-synthesizing enzymes, glutamic acid decarboxylase (GAD) 65 and GAD 67, in the spinal dorsal horns (DHs) were analyzed using Western blot and immunohistochemistry comparing responders and nonresponders to SCS, with and without SCS, as well as controls. RESULTS: There were no significant differences in general DH GAD levels between hypersensitive, nonhypersensitive, and intact control animals. Although SCS did not significantly influence these levels, there was a significant local augmentation of GAD 65 expression in lamina II in SCS responders subjected to SCS immediately prior to tissue collection as compared with SCS nonresponders. CONCLUSIONS: Although GABAergic mechanisms are closely related to the effects of SCS, the presence of neuropathic signs and their suppression by SCS are not associated with changes of the general levels of the spinal DH GABA-synthesizing enzymes. However, in SCS responding animals, there was a significant increased expression of GAD 65 in lamina II, presumably reflecting an augmented GABA synthesis following SCS.

A narrative history of the International Society for Psychiatric Surgery: 1970-1983.

In order to reconcile the present resurgence of psychiatric neurosurgery with the not-too-distant historic transgressions in the field, one needs to examine the era of transition from crude art to regulated science. In large part, this transition took place in the 1970s with the continued development and widespread acceptance of stereotactic techniques in functional neurosurgery and several hard-fought ideological and academic victories by proponents of the much-maligned field. Established in 1970, the International Society for Psychiatric Surgery (ISPS) sought to gather like-minded surgeons, psychiatrists and other neuroscientists to counter the rising pressure from special interest groups, as well as some in the public and medical realm, who attempted to abolish all forms of surgical management of psychiatric disease. We reviewed the archives of the ISPS, including letters from its founding members and active participants, conference proceedings and minutes from organizational meetings, from throughout its existence from 1970 to 1983. The archives provide a unique insight into the organization and objectives of the society that kept psychiatric surgery alive in the face of persistent and staunch opposition. We also outline the lessons that current and future functional neurosurgeons can learn from the ISPS, whose key figures, structure and communication, in the non-electronic era, were instrumental for the survival of psychiatric surgery during that critical period.

The interaction between antidepressant drugs and the pain-relieving effect of spinal cord stimulation in a rat model of neuropathy.

BACKGROUND: Spinal cord stimulation (SCS) has proven to be a valuable treatment in neuropathic pain. On the basis of our previous studies on the mode of action of SCS, intrathecal administration of subeffective doses of certain drugs has been shown to enhance the pain-relieving effect in patients with SCS. Antidepressants have a well-established beneficial effect in neuropathic pain. We performed the present study to examine potential synergistic or antagonistic effects on SCS of antidepressants: amitriptyline (tricyclic antidepressant), fluoxetine (selective serotonin reuptake inhibitor), and milnacipran (selective serotonin/noradrenaline reuptake inhibitor). METHODS: In rats, the effect of SCS on mechanical hypersensitivity after peripheral nerve injury was assessed in awake, freely moving animals. Antidepressants were administered intrathecally. RESULTS: When combining SCS with subeffective doses of amitriptyline or milnacipran, the suppressive effect of SCS on the mechanical hypersensitivity was enhanced in comparison with that obtained with SCS alone. There was no detectable effect of fluoxetine. No signs of an antagonistic effect of the drugs on the SCS effect were observed. CONCLUSIONS: These findings suggest a possible clinical application with a combination of SCS and a tricyclic antidepressant or selective serotonin/noradrenaline reuptake inhibitor drug in cases in which SCS per se has proven inefficient.

Spinal 5-HT receptors that contribute to the pain-relieving effects of spinal cord stimulation in a rat model of neuropathy.

Spinal cord stimulation (SCS) is extensively employed in the management of neuropathic pain, but the underlying mechanisms are only partially understood. Recently, we demonstrated that the pain-relieving effect of SCS appears to involve the spinal serotonin system, and the present study aimed at identifying the types of the spinal serotonin receptors involved. Experiments were performed on rats with neuropathy produced by partial ligation of the sciatic nerve. Tactile sensitivity was assessed using von Frey filaments, and cold and heat sensitivity with cold spray and radiant heat, respectively. Selective 5-HT receptor antagonists, methiothepin (5-HT(1,6,7)), ketanserin tartrate (5-HT(2A)), TICM (5-HT(3)), SDZ-205,557 (5-HT(4)), as well as receptor agonists, α-m-5-HT (5-HT(2)), m-CPBG (5-HT(3)) in per se ineffective doses, or vehicle, were administrated intrathecally 5 minutes prior to the application of SCS. Ketanserin and SDZ-205,557 significantly attenuated the suppressive effect of SCS on tactile hypersensitivity, while methiothepin and TICM were ineffective. The suppressive effect on cold hypersensitivity of SCS was counteracted by ketanserin only. None of the 5-HT receptor antagonists attenuated the suppressive effect on heat hyperalgesia of SCS. Subeffective doses of α-m-5-HT and m-CPBG enhanced the suppressive effect of SCS on tactile hypersensitivity. The enhancing effect of m-CPBG was abolished by a γ-aminobutyric acid (GABA)(A) or GABA(B) antagonist intrathecally. These results suggest that the activation of 5-HT(2A), 5-HT(3), and 5-HT(4) receptors plays an important role in SCS-induced relief of neuropathic pain. The activation of 5-HT(3) receptors appears to operate via spinal GABAergic interneurons.

Intrathecal clonidine and baclofen enhance the pain-relieving effect of spinal cord stimulation: a comparative placebo-controlled, randomized trial.

OBJECTIVE: Spinal cord stimulation (SCS) is a well-established treatment for neuropathic pain; nevertheless, 40% of patients fail to obtain satisfactory pain relief and in many patients, the effect tends to diminish with time. Based on animal experiments, intrathecal baclofen was previously introduced clinically to enhance suboptimal SCS effects. Later animal experiments demonstrated similar data for clonidine. The aim of this study was to elucidate whether intrathecal clonidine or baclofen enhances the effect of SCS in neuropathic pain patients in whom the pain relieving-effect of SCS is inadequate. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted with 10 patients experiencing neuropathic pain with insufficient pain relief with SCS alone. Clonidine, baclofen, and saline (control) were intrathecally administered by bolus injections in combination with SCS. RESULTS: Seven of 10 patients reported significant pain reduction when SCS was combined with active drugs. The mean visual analog scale ratings were reduced by more than 50% with either drug combined with SCS. Four patients previously treated with SCS alone later underwent implantation of a pump for long-term administration of clonidine or baclofen. In the 2 patients with clonidine pumps with a mean follow-up of 15 months, the combined therapy produced pain reduction of 55% and 45%, respectively. The corresponding effect with baclofen was 32% and 82%, respectively, at 7 months follow-up. CONCLUSION: A trial with clonidine and baclofen combined with SCS may be warranted in patients who do not obtain satisfactory pain relief with SCS alone or experienced a decreasing therapeutic effect.

Pain relief by spinal cord stimulation involves serotonergic mechanisms: an experimental study in a rat model of mononeuropathy.

The aim of the present study was to examine the role of the spinal serotonergic system in the pain relieving effect of spinal cord stimulation (SCS) using a rat model of mononeuropathy. Tactile withdrawal thresholds, cold responses and heat withdrawal latencies were assessed before and after SCS. In some rats, SCS produced an attenuation of the hypersensitivity following nerve injury (SCS responding rats). When SCS was applied immediately prior to sacrifice, the 5-HT content in the dorsal quadrant of the spinal cord ipsilateral to the nerve injury was increased in SCS responding rats. But there was no change in responding rats without stimulation, or in SCS non-responding rats with or without stimulation or in controls. Immunohistochemical examination showed a high density of 5-HT stained terminals in the dorsal horn superficial laminae (I-II) in SCS responding rats following stimulation. It was also found that i.t. administration of a sub-effective dose of serotonin in SCS non-responding rats markedly enhanced the pain relieving effect of SCS on tactile and cold hypersensitivity, while there was no effect on heat hyperalgesia. This enhanced effect on tactile hypersensitivity could be partially blocked by a GABA(B) receptor antagonist (CGP 35348) but not by a muscarinic M(4) receptor antagonist (Muscarinic toxin 3) administered i.t. shortly before the 5-HT injection. In conclusion, there is evidence that the spinal 5-HT system plays an important role in the mode of action of SCS involving the activation of descending serotonergic pathways that may inhibit spinal nociceptive processing partially via a GABAergic link.

Capsulotomy for obsessive-compulsive disorder: long-term follow-up of 25 patients.

CONTEXT: Capsulotomy is sometimes used as a treatment of last resort in severe and treatment-refractory cases of obsessive-compulsive disorder (OCD). OBJECTIVE: To evaluate the long-term efficacy and safety of capsulotomy in OCD. DESIGN: Noncontrolled, long-term follow-up trial (mean of 10.9 years after surgery). SETTING: University hospital referral center. PATIENTS: Twenty-five consecutive patients with OCD who underwent capsulotomy from 1988 to 2000. INTERVENTION: Unilateral or bilateral capsulotomy. Lesions were created by means of radiofrequency heating (thermocapsulotomy) or gamma radiation (radiosurgery, gammacapsulotomy). MAIN OUTCOME MEASURE: Yale-Brown Obsessive-Compulsive Rating Scale (Y-BOCS) score. RESULTS: The mean Y-BOCS score was 34 preoperatively and 18 at long-term follow-up (P < .001). Response (defined as > or = 35% reduction at long-term follow-up compared with baseline) was seen in 12 patients at long-term follow-up. Nine patients were in remission (Y-BOCS score, < 16) at long-term follow-up. Only 3 patients were in remission without adverse effects at long-term follow-up. Response rates did not differ significantly between surgical methods. A mean weight gain of 6 kg was reported in the first postoperative year. Ten patients were considered to have significant problems with executive functioning, apathy, or disinhibition. Six of these 10 patients had received high doses of radiation or had undergone multiple surgical procedures. Results of our magnetic resonance imaging analysis in 11 patients suggest that the OCD symptom reduction may be increased by reducing the lateral extension of the lesions, and a reduction in the medial and posterior extension may limit the risk of adverse effects (ie, smaller lesions may produce better results). CONCLUSIONS: Capsulotomy is effective in reducing OCD symptoms. There is a substantial risk of adverse effects, and the risk may vary between surgical methods. Our findings suggest that smaller lesions are safer and that high radiation doses and multiple procedures should be avoided.

Long-term electrical capsular stimulation in patients with obsessive-compulsive disorder.

OBJECTIVE: Because of the irreversibility of lesioning procedures and their possible side effects, we studied the efficacy of replacing bilateral anterior capsulotomy with chronic electrical capsular stimulation in patients with severe, long-standing, treatment-resistant obsessive-compulsive disorder. METHODS: We stereotactically implanted quadripolar electrodes in both anterior limbs of the internal capsules into six patients with severe obsessive-compulsive disorder. Psychiatrists and psychologists performed a double-blind clinical assessment. A blinded random crossover design was used to assess four of those patients, who underwent continuous stimulation thereafter. RESULTS: The psychiatrist-rated Yale-Brown Obsessive Compulsive Scale score was lower in the stimulation-on condition (mean, 19.8 +/- 8.0) than in the postoperative stimulator-off condition (mean, 32.3 +/- 3.9), and this stimulation-induced effect was maintained for at least 21 months after surgery. The Clinical Global Severity score decreased from 5 (severe; standard deviation, 0) in the stimulation-off condition to 3.3 (moderate to moderate-severe; standard deviation, 0.96) in the stimulation-on condition. The Clinical Global Improvement scores were unchanged in one patient and much improved in the other three during stimulation. During the stimulation-off period, symptom severity approached baseline levels in the four patients. Bilateral stimulation led to increased signal on functional magnetic resonance imaging studies, especially in the pons. Digital subtraction analysis of preoperative [(18)F]2-fluoro-2-deoxy-d-glucose positron emission tomographic scans and positron emission tomographic scans obtained after 3 months of stimulation showed decreased frontal metabolism during stimulation. CONCLUSION: These observations indicate that capsular stimulation reduces core symptoms 21 months after surgery in patients with severe, long-standing, treatment-refractory obsessive-compulsive disorder. The stimulation elicited changes in regional brain activity as measured by functional magnetic resonance imaging and positron emission tomography.

Subthalamic stimulation for essential tremor. Short- and long-term results and critical target area.

BACKGROUND/AIMS/METHODS: In order to explore the usefulness and long-term result of subthalamic nucleus (STN) stimulation for the treatment of essential tremor (ET), we evaluated 3 groups of patients undergoing deep brain stimulation (DBS) for ET. RESULTS: Group 1 consisted of 3 patients who 9 years ago at intra-operative testing had good tremor reduction from STN stimulation. The second group consisted of 10 patients treated with DBS in the ventral intermediate (Vim) nucleus of the thalamus. The third group comprised 9 patients subjected to STN stimulation for ET with 1-3 years of follow-up. The 3 ET patients with STN stimulation in group 1 have continued to have excellent tremor reduction for up to 9 years. The second group, with Vim stimulation, showed less favourable long-term results. All of the recent STN stimulation group experienced good tremor reduction, but some of the patients above 70 years of age reported troublesome side effects. CONCLUSION: Provided that intra-operative test stimulation produces satisfactory tremor control, STN is a good target for long-term treatment of ET. For patients above the age of 70 years, however, the Vim is a preferable target.

Cholinergic mechanisms involved in the pain relieving effect of spinal cord stimulation in a model of neuropathy.

The mechanisms underlying the pain relieving effect of spinal cord stimulation (SCS) on neuropathic pain remain unclear. We have previously demonstrated that suppression of tactile hypersensitivity produced by SCS may be potentiated by i.t. clonidine in a rat model of mononeuropathy. Since the analgesic effect of this drug is mediated mainly via cholinergic mechanisms, a study exploring the possible involvement of the spinal cholinergic system in SCS was undertaken. The effect of SCS was assessed with von Frey filaments in rats displaying tactile hypersensitivity after partial ligation of the sciatic nerve and both SCS-responding and non-responding as well as normal rats were subjected to microdialysis in the dorsal horn. Acetylcholine (ACh) was analyzed with HPLC before, during and after SCS. SCS produced significantly increased release of ACh in the dorsal horn in rats responding to SCS whereas the release was unaffected in the non-responding animals. Furthermore, the basal release of ACh was significantly lower in nerve lesioned than in normal rats. In another group of rats it was found that the response to SCS was completely eliminated by i.t. atropine and a muscarinic M(4) receptor antagonist while a partial attenuation was produced by M(1) and M(2) antagonists. Blocking of nicotinic receptors did not influence the SCS effect. In conclusion, the attenuating effect of SCS on pain related behavior is associated with the activation of the cholinergic system in the dorsal horn and mediated via muscarinic receptors, particularly M(4,) while nicotinic receptors appear not to be involved.

Muscarinic receptor activation potentiates the effect of spinal cord stimulation on pain-related behavior in rats with mononeuropathy.

Spinal cord stimulation (SCS) has proven to be a valuable treatment in neuropathic pain. Our previous animal experiments performed on rat models of SCS and ensuing clinical trials have demonstrated that intrathecal (i.t.) administration of subeffective doses of certain drugs may enhance the pain relieving effect of SCS in cases with unsatisfactory SCS outcome. Recently, an augmented release of spinal acetylcholine acting on muscarinic receptors has been shown to be one of the mechanisms involved in SCS. The present study was performed to examine whether cold hypersensitivity and heat hyperalgesia in rats with partial sciatic nerve injuries can be attenuated by SCS in the same way as tactile hypersensitivity and to explore a possibly synergistic effect of SCS and a muscarinic receptor agonist, oxotremorine. Rats with signs of neuropathy were subjected to SCS applied in awake, freely moving condition. Oxotremorine was administered intrathecally. Tactile, cold and heat sensitivities were assessed by using von Frey filaments, cold spray and focused radiant heat, respectively. Oxotremorine i.t. dose-dependently suppressed the tactile hypersensitivity. SCS markedly increased withdrawal thresholds (WTs), withdrawal latencies and cold scores. When combining SCS with a subeffective dose of oxotremorine i.t., the suppressive effect of SCS on the pain-related symptoms was dramatically enhanced in rats failing to obtain a satisfactory effect with SCS alone. In conclusion, the combination of SCS and a drug with selective muscarinic receptor agonistic properties could be an optional therapy, when SCS per se has proven inefficient.

Spinal cord stimulation in adolescents with complex regional pain syndrome type I (CRPS-I).

Complex regional pain syndrome type I (CRPS-I) is not uncommon in children, particularly in adolescent girls. Most often, the condition involves a foot and is characterized by spontaneous pain, tactile allodynia and dysautonomic signs. There is usually a history of a minor, local trauma but sometimes no reasonable cause can be identified, and there are no signs of persistent tissue injury giving rise to ongoing nociception. Common analgesics are generally of no benefit, and the standard treatment includes sociopsychological support, physiotherapy, tricyclic antidepressants and antiepileptic drugs, sympathetic blocks (SB), and cognitive-behavioural therapy. For a minority of patients who prove to be resistant to such therapies, spinal cord stimulation (SCS) may be tried. The present study comprises seven girls, 11-14 years of age, presenting with severe, incapacitating and therapy-resistant CRPS-I, who were subjected to SCS. In two of them, percutaneous electrode implantation had to be performed in general anaesthesia. Trial stimulation was performed in all, but one. In two cases, it was not possible to produce paraesthesias that entirely covered the pain area. A pain relieving effect of SCS was usually not reported until after 1-2 weeks of trial stimulation. After another 2-6 weeks, pain alleviation was complete in five of the seven patients, one to eight years after the intervention. In one case, a local infection necessitated the removal of the electrode; nevertheless a few days of trial stimulation produced substantial pain relief that still persists. In four patients, the SCS use was gradually diminished and eventually the device could be removed. The favourable outcome in all seven cases with no or minor remaining symptoms and without severe recurrences illustrates that SCS may also be an efficient treatment in paediatric cases with exceptionally therapy resistant forms of CRPS I.

Baclofen-enhanced spinal cord stimulation and intrathecal baclofen alone for neuropathic pain: Long-term outcome of a pilot study.

In a previously published pilot study, we addressed the possibility to increase the effectiveness of spinal cord stimulation (SCS) applied for neuropathic pain by using adjunct pharmacological therapy. This combined treatment approach was a direct spin-off from animal experiments aiming at the exploration of transmitter and receptor mechanisms involved in the pain relieving effect of SCS. Out of 48 patients with neuropathic pain of peripheral origin responding poorly to SCS, seven received pumps for intrathecal baclofen (GABA-B receptor agonist) delivery together with SCS, and four had pumps alone. In order to assess the long-term effect a follow-up has been performed, with an average, total treatment time of 67 months. At the follow-up the remaining nine patients still enjoy about the same pain relief as initially, but with a mean, further dose increase of about 30%. This study demonstrates that a deficient SCS effect in neuropathic pain may be considerably improved by intrathecal baclofen administration, and that this enhanced effect persists for a long-time. On-going and future animal studies may provide new and even more efficient pharmaceutical candidates for such combined therapy.

Mode of action of spinal cord stimulation in neuropathic pain.

Spinal cord stimulation emerged as a spin-off from the classical gate-control theory, which, however, does not suffice to explain its clinical effects. Whether or not nociceptive forms of pain may be attenuated remains a controversial issue. Previous experimental studies aiming at elucidating the underlying mechanisms were performed on intact, anesthetized animals and were therefore of limited clinical relevance. Not until recent years have some data on the mode of action accumulated providing evidence that gamma-aminobutyric acid (GABA) ergic as well as adenosine-related mechanisms are involved in the pain amelioration. It appears that the effects are exerted mostly via segmental spinal levels, but recent evidence suggests that a supraspinal loop may also be of importance; this issue remains to be resolved. It should be emphasized that most experimental data pertaining to the mode of action are derived from so-called animal models of neuropathic pain. However, caution must be exercised in the translation of such data from bench to bedside, because some behavioral signs interpreted as "pain" in such models may be misleading. We still need animal studies to generate basic data but these findings should also be confirmed in humans.

Response to spinal cord stimulation in variants of the spared nerve injury pain model.

Spinal cord stimulation (SCS) is a treatment given to patients with drug-resistant neuropathic pain, in particular pain resulting from peripheral nerve injury. However, the reasons why some patients develop neuropathic pain and why SCS is not effective in all patients with this chronic pain are not fully understood. The present study compares the response to SCS and the yield of neuropathic animals in variants of the spared nerve injury (SNI) model introduced by Decosterd and Woolf (I. Decosterd, C.J. Woolf, Spared nerve injury: an animal model of persistent peripheral neuropathic pain, Pain 87 (2000) 149-158). Sprague-Dawley rats were prepared with various types of lesions of different branches of the sciatic nerve and then tested for paw mechanical hypersensitivity. A miniature electrode system for SCS was implanted at the T10-T11 vertebral level. Stimulation was applied in awake, freely moving animals with parameters comparable to those employed clinically. Suppression of paw hypersensitivity was considered a positive response to SCS. The incidence of mechanical hypersensitivity ("allodynia") in the different models was: SNI 53%; peroneal axotomy 45%; tibial axotomy 68%; tibial tight ligation 73% and partial tibial tight ligation 50%. "Mirror phenomena" with contralateral paw hypersensitivity was present in about 20% of the animals. The response to SCS differed between models with the lowest response rate in the original SNI model (8%) while the others demonstrated rates in the order of 40-50%. There was a tendency that the efficacy of SCS in suppressing allodynia was inversely related to the severity of hypersensitivity. In conclusion, modifications of the SNI model provide a reproducible incidence of neuropathic hypersensitivity and an increased responsiveness to SCS. These variants may prove suitable for future research on the mechanisms involved in pain relief with SCS.