Layout pattern analysis and coverage evaluation in computational lithography.

In advanced semiconductor technology nodes, the model accuracy of optical proximity correction (OPC) is the key for integrated circuit (IC) chip mask tape out, yield ramp up, and product time-to-market. An accurate model means a small prediction error for the full chip layout. As the full chip layout usually has large pattern variety, an optimal pattern set with good coverage is desired during the model calibration process. Currently, no existing solutions can provide the effective metrics to evaluate the coverage sufficiency of the selected pattern set before a real mask tape out, which may potentially cause higher re-tape out cost and product time-to-market delay due to the multiple rounds of model calibration. In this paper, we construct the metrics to evaluate the pattern coverage before any metrology data is obtained. The metrics are based on either the pattern's intrinsic, numerical feature representation, or its potential model simulation behavior. Experimental results show a positive correlation between these metrics and lithographic model accuracy. An incremental selection method is also proposed based on the pattern simulation error. It reduces up to 53% of the model's verification error range. These pattern coverage evaluation methods can improve the efficiency of OPC model building, and are, in turn, beneficial to the whole OPC recipe development process.

Omental Flap for Complex Sternal Wounds and Mediastinal Infection Following Cardiac Surgery.

INTRODUCTION: Omental flap (OF) is a traditional surgical option to counteract severe postcardiotomy mediastinal infection and to cover extensive sternal defects. We reviewed our experience with omental flap transfer (OFT) in various clinical circumstances, in which omentoplasty may be considered by cardiac surgeons. METHODS: Twenty-one patients, who underwent OFT from January 2012 to December 2021, were studied. The main indication was treatment of infected foreign material implants including vascular grafts and ventricular assist devices or prevention of its infection (16 patients). In five patients, an OFT was used to cure mediastinitis following deep sternal wound infection after median sternotomy. RESULTS: All patients had a high surgical risk with 3 ± 1.9 previous sternotomies and a mean Euro Score II of 55.0 ± 20.1. OF was successful in its prophylactic or therapeutic purpose in all patients, no complications related to the operative procedure were noted, that is, no early or late flap failure and no herniation of abdominal organs occurred. In-hospital mortality was six patients as three patients each died from multiple organ dysfunction syndrome and cerebral hemorrhage. All fifteen patients discharged demonstrated rapid recovery, complete wound healing without fistula, and no late gastrointestinal complications. The mean follow-up of 18 months was uneventful. CONCLUSION: OFT seems to be an excellent solution for extensive mediastinal and deep sternal wound infections.

Impact of fluid balance and blood transfusion during extracorporeal circulation on outcome for acute type A aortic dissection surgery.

BACKGROUND: In thoracic aortic surgery, fluid replacement and blood transfusion during extracorporeal circulation (ECC) are associated with increased coagulopathy, elevated inflammatory response, and end-organ dysfunction. The optimal strategy has not been established in this regard. The aim of this study was to evaluate the effect of the fluid balance during ECC in thoracic aortic dissection surgery on outcome. METHODS: Between 2009 and 2020, 358 patients suffering from acute type A aortic dissection (ATAAD) underwent aortic surgery at our heart center. In-hospital mortality, major complications (postoperative stroke, respiratory failure, heart failure, acute renal failure), and follow-up mortality were assessed. Logistic regression analysis was used to identify whether fluid balance and blood transfusion during ECC were risk factors for occurring adverse events. RESULTS: The in-hospital mortality amounted to 20.4%. Major complications included temporary neurologic deficit in 13.4%, permanent neurologic deficit in 6.1%, acute renal failure in 32.7%, prolonged ventilation for respiratory failure in 17.9%, and acute heart failure in 10.9% of cases. At a mean of 42 months after discharge of 285 survivors, follow-up mortality was 13.3%. Multivariate analysis revealed major complications as well as the risk of in-hospital and follow-up mortality to increase with fluid balance and blood transfusion during ECC. CONCLUSIONS: Fluid balance and blood transfusion during ECC present with predictive potential concerning the risk of postoperative adverse events.

Genetic Characteristics of Resectable Colorectal Cancer with Pulmonary Metastasis.

The lung is the most common extra-abdominal metastasis site of colorectal cancer (CRC). This study aimed to investigate the genetic variation of pulmonary metastases (PM) and primary tumors in resectable CRC. The clinical data of 410 patients with PM after CRC surgery and 33 paraffin-embedded tissue samples from January 2012 to July 2019 in our hospital were collected retrospectively. Next, 450-panel gene detection technologies based on next-generation sequencing (NGS) were used to analyze the changes in the gene map and the overall variation in cancer-related genes in PM and primary tumors. After quality control, 19 samples were included in the final gene analysis. The results showed that APC (89.5%), TP53 (89.5%), and KRAS (53%) were the most common mutations in PM and primary tumors, but the gene amplification variation was enriched in primary tumors (4.6% vs. 11.4%). KRAS G12D was the most common site variation of the KRAS gene in both PM and primary tumors of CRC. There was no hotspot mutation in the TP53 locus in CRC, and the TP53 mutation in the PM was consistent with that in the primary lesion. The microsatellite instability (MSI) levels of 10 patients were MSS. The mean tumor mutation burden (TMB) of the primary tumor (5.3 muts·Mb-1) was slightly higher than that of metastasis (5.0 muts·Mb-1). In our institution, the genetic characteristics of resectable PM from CRC may be highly consistent with those of the primary tumor.

The Influence of Radiological "Disappearing Lesions" on the Efficacy and Prognosis of Patients with Colorectal Liver Metastases Undergoing Conversion Therapy.

PURPOSE: The purpose of the current study was to analyze the influence of radiological "disappearing liver metastasis" (DLM) on the efficacy and prognosis of patients with colorectal liver metastases (CRLM) undergoing conversion therapy. METHODS: Patients with CRLM by the multidisciplinary team (MDT) of the First Affiliated Hospital of Chongqing Medical University were retrospectively enrolled from January 2014 to January 2021. The relationship between the occurrence and recurrence of DLM and different clinical factors was analyzed. RESULTS: Thirty-five of the 113 patients (31.0%) with initially unresectable CRLM developed DLM, and of the 361 lesions, 177 disappeared (49.0%). Within 6 months, 6-12 months, and 12-24 months groups, the recurrence rate was 3.4%, 16.8%, and 34.8%, but there is no recurrence in after 24 months group. There was a statistical difference between chemotherapy alone and chemotherapy combined with the targeted therapy group on the occurrence of DLM (58.3% vs. 37.1%, P < 0.001). There were significant differences between <5 mm group and >10 mm group on occurrence of DLM（76.7% vs. 30.4%, P < 0.001) and between 5-10 mm group and >10 mm group also (70.0% vs. 30.4%, P < 0.001). Through univariate and multivariate analyses, it was concluded that age (P = 0.026, 95%CI = 3.690) and treatment regimens (P = 0.033, 95%CI = 2.703) had a significant influence on the progression-free survival (PFS) time of DLM. CONCLUSION: Younger patients, who use chemotherapy alone to achieve a therapeutic effect, might have better survival benefits when the lesions do not progress within 2 years after the appearance of DLMs.

Short-Term Clinical and Oncological Outcome of Prolonging Operation Interval After Neoadjuvant Chemoradiotherapy for Locally Advanced Middle and Low Rectal Cancer.

PURPOSE: The purpose of this study is to evaluate the short-term clinical and oncological outcome of prolonging operation interval to 11 weeks after the end of radiotherapy for locally advanced middle and low rectal cancer. METHODS: A total of 123 patients with stage II/III (cT3/T4 or N+) low and middle rectal cancer who had undergone operation after neoadjuvant chemoradiotherapy were selected. According to the interval time between the last radiotherapy and operation, they were assigned to a short-interval group (SG, <11 weeks, n=66) and long-interval group (LG, ≥11 weeks, n=57). The relations among interval time and short-term clinical outcome and oncological outcome were analyzed. RESULTS: The analysis found that basic information, clinical characteristics, and preoperative treatment between the two groups had no significant difference. There were no differences in operation time, estimated intraoperative blood loss and postoperative complications. The rate of sphincter preservation in the low and middle rectum was 66.7% in the short-interval group and 59.7% in the long-interval group (P=0.42). The incidence of anastomotic leak in the long-interval group was higher than that in the short-interval group (P=0.08). There was no significant difference in the recovery time of intestinal function and median duration of hospitalization between the two groups. The pathological complete remission rate was 17.07%. Multivariate analysis showed interval time had no influence on pathological complete remission. There was no significant difference in 3-year overall survival and 3-year disease-free survival between the two groups. The risk of recurrence and metastasis in patients with positive lymph nodes was higher than those with negative lymph nodes (P<0.05), HR=4.812 (95% CI 2.4-9.648). CONCLUSION: Prolonging the interval time of operation to 11 weeks after neoadjuvant chemoradiotherapy for middle and low rectal cancer does not improve the pathologic complete remission, morbidity, and mortality. There was no significant effect on oncologic outcome after prolonging the operation interval. Therefore, it is safe to prolong the interval of operation to 11 weeks.

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.

Inverse lithography source optimization via compressive sensing.

Source optimization (SO) has emerged as a key technique for improving lithographic imaging over a range of process variations. Current SO approaches are pixel-based, where the source pattern is designed by solving a quadratic optimization problem using gradient-based algorithms or solving a linear programming problem. Most of these methods, however, are either computational intensive or result in a process window (PW) that may be further extended. This paper applies the rich theory of compressive sensing (CS) to develop an efficient and robust SO method. In order to accelerate the SO design, the source optimization is formulated as an underdetermined linear problem, where the number of equations can be much less than the source variables. Assuming the source pattern is a sparse pattern on a certain basis, the SO problem is transformed into a l1-norm image reconstruction problem based on CS theory. The linearized Bregman algorithm is applied to synthesize the sparse optimal source pattern on a representation basis, which effectively improves the source manufacturability. It is shown that the proposed linear SO formulation is more effective for improving the contrast of the aerial image than the traditional quadratic formulation. The proposed SO method shows that sparse-regularization in inverse lithography can indeed extend the PW of lithography systems. A set of simulations and analysis demonstrate the superiority of the proposed SO method over the traditional approaches.

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.

Hybrid source mask optimization for robust immersion lithography.

To keep pace with the shrinkage of critical dimension, source and mask optimization (SMO) has emerged as a promising resolution enhancement technique to push the resolution of 193 nm argon fluoride immersion lithography systems. However, most current pixelated SMO approaches relied on scalar imaging models that are no longer accurate for immersion lithography systems with hyper-NA (NA>1). This paper develops a robust hybrid SMO (HSMO) algorithm based on a vector imaging model capable of effectively improving the robustness of immersion lithography systems to defocus and dose variations. The proposed HSMO algorithm includes two steps. First, the individual source optimization approach is carried out to rapidly reduce the cost function. Subsequently, the simultaneous SMO approach is applied to further improve the process robustness by exploiting the synergy in the joint optimization of source and mask patterns. The conjugate gradient method is used to update the source and mask pixels. In addition, a source regularization approach and source postprocessing are both used to improve the manufacturability of the optimized source patterns. Compared to the mask optimization method, the HSMO algorithm achieves larger process windows, i.e., extends the depth of focus and exposure latitude, thus more effectively improving the process robustness of 45 nm immersion lithography systems.

Block-based mask optimization for optical lithography.

Pixel-based optical proximity correction (PBOPC) methods have been developed as a leading-edge resolution enhancement technique (RET) for integrated circuit fabrication. PBOPC independently modulates each pixel on the reticle, which tremendously increases the mask's complexity and, at the same time, deteriorates its manufacturability. Most current PBOPC algorithms recur to regularization methods or a mask manufacturing rule check (MRC) to improve the mask manufacturability. Typically, these approaches either fail to satisfy manufacturing constraints on the practical product line, or lead to suboptimal mask patterns that may degrade the lithographic performance. This paper develops a block-based optical proximity correction (BBOPC) algorithm to pursue the optimal masks with manufacturability compliance, where the mask is shaped by a set of overlapped basis blocks rather than pixels. BBOPC optimization is formulated based on a vector imaging model, which is adequate for both dry lithography with lower numerical aperture (NA), and immersion lithography with hyper-NA. The BBOPC algorithm successively optimizes the main features (MF) and subresolution assist features (SRAF) based on a modified conjugate gradient method. It is effective at smoothing any unmanufacturable jogs along edges. A weight matrix is introduced in the cost function to preserve the edge fidelity of the printed images. Simulations show that the BBOPC algorithm can improve lithographic imaging performance while maintaining mask manufacturing constraints.

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.

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.

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.

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.