Microneurographic findings of relevance to pain in patients with erythromelalgia and patients with diabetic neuropathy

Mechanisms responsible for neuropathic pain are still unclear. By using microneurography we have been able to record from single C-nociceptive and sympathetic fibers in patients and attempted to uncover possible abnormal functional properties of these fibers of relevance for pain. In two previously published studies conducted on patients with erythromelalgia and patients with diabetic neuropathy, some of the major findings were: (1) spontaneous activity in nociceptive fibers, (2) sensitization of mechano-insensitive C-fibers, and (3) an altered distribution of C-afferent nerve fibers with a reversal of the proportion of the two main subtypes of C-nociceptive fibers, indicating a loss of function of polymodal nociceptors. Although some degree of spontaneous activity and sensitization also was found in patients without pain, these mechanisms may still be of importance for the development and maintenance of neuropathic pain. A change in the distribution of C-nociceptive fibers in the skin as shown in the patients with diabetic neuropathy may help to reveal mechanisms responsible for small-fiber dysfunction.     

A study of the sympathetic skin response and sensory nerve action potential after median and ulnar nerve repair

The purpose of this study was to compare SSR with sensory nerve action potential (SNAP) responses in regeneration of injured peripheral nerves after nerve repair. We studied 10 male patients with a mean age of 26.7 years. All the patients had complete laceration of median or ulnar nerves. The patients were followed up at least for six months. SSR and SNAP assessment were performed every one to two months. Normal hands were used as controls. SSR was positive after 15.8 +/- 9.4 weeks (mean +/- 2 SD) and SNAP after 27.8 +/- 12.9 weeks (mean +/- 2 SD). The difference was statistically significant (P value < 0.001). This can be due to more rapid growth of sympathetic unmyelinated fibers relative to sensory myelinated fibers. This study also shows that recovery of the sudomotor activity following nerve repair is satisfactory in general and SSR can be used as a useful and sensitive method in the evaluation of sudomotor nerve regeneration.     

The respiratory cycle modulates brain potentials,sympathetic activity,and subjective pain sensation induced by noxious stimulation

To test the hypothesis that a respiratory cycle influences pain processing, we conducted an experimental pain study in 10 healthy volunteers. Intraepidermal electrical stimulation (IES) with a concentric bipolar needle electrode was applied to the hand dorsum at pain perceptual threshold or four times the perceptual threshold to produce first pain during expiration or inspiration either of which was determined by the abrupt change in an exhaled CO₂ level. IES-evoked potentials (IESEPs), sympathetic skin response (SSR), digital plethysmogram (DPG), and subjective pain intensity rating scale were simultaneously recorded. With either stimulus intensity, IES during expiration produced weaker pain feeling compared to IES during inspiration. The mean amplitude of N200/P400 in IESEPs and that of SSR were smaller when IES was applied during expiration. The magnitude of DPG wave gradually decreased after IES, but a decrease in the magnitude of DPG wave was less evident when IES was delivered during expiration. Regardless of stimulus timing or stimulus intensity, pain perception was always concomitant with appearance of IESEPs and SSR, and changes in DPG. Our findings suggest that pain processing fluctuates during normal breathing and that pain is gated within the central nervous system during expiration.     

The effect of transcutaneous electrical nerve stimulation on sympathetic skin response

The aim of present study was to determine whether combination of transcutaneous electrical nerve stimulation (TENS) and acupuncture inhibits sympathetic nerve activity in healthy humans. Multiunit efferent postganglionic sympathetic activity was recorded with Toennies set. In this study, the aim was to obtain latency, amplitude and duration of sympathetic skin response (SSR) and skin temperature (ST) from both hands in 15 healthy subjects. Subjects randomly assigned and everybody participated in all the three groups [Control Group (CG), Acupuncture Group (AG) and Nerve Stimulation Group (NSG)]. TENS (2 Hz, 250 microsecond) was applied over the median nerve of the right elbow in NSG for 20 min, either, TENS was applied over (HE-7) point of the right hand in CG (TENS off) and AG (TENS on) for 20 min. SSR (lat, amp, dur) and ST data was recorded before TENS and for immediate, 5 min and 10 min post--TENS. ST was recorded in distal phalanx of index finger of both hands and SSR was recorded from both hands. TENS in CG did not affect ST and SSR following stimulation. TENS applied at AG and NSG caused a significant increase in ST (P = 0.001), significant increase in latency of SSR (P = 0.001), significant decrease in amplitude of SSR (P = 0.001) and no significant changes were observed in duration of SSR (P > 0.05). Then statistical analysis showed differences between both of groups (AG & NSG) for ST and SSR post--TENS. Transcutaneous electrical nerve stimulation inhibits sympathetic nerve activity in healthy humans.     

Sympathetic skin response in diabetic neuropathy

Autonomic neuropathy is a complication of diabetes mellitus (DM) in substantial proportion of cases and may cause definite autonomic symptoms. Because conventional electrophysiological methods do not assess the autonomic nervous system, simple reproducible tests were developed. One of them is sympathetic skin response (SSR) which provides useful information about the status of sympathetic postganglionic function. The aim of this study is to perform SSR in diabetic patients to see whether this test can be used as an electrophysiological method for the diagnosis and confirmation of diabetic autonomic neuropathy. 20 diabetic patients who had electrophysiologically confirmed polyneuropathy but showed no symptoms or signs referable to autonomic system dysfunction were included. 14 (70%) patients demonstrated abnormal SSR. 2 abnormal patterns were observed. An absent response in at least one tested lower extremity (50%) and prolonged foot with normal hand latency (20%). 6 patients (30%) demonstrated no abnormalities. Foot and hand latencies in diabetics did not differ significantly from those of normal controls (p: 0.4, p: 0.1) and no correlation could be found with latencies and duration of sickness, patient's age and HbA1c values. We believe latency measurement is an objective measure of conduction in multineural pathways and can detect subclinical involvement of sympathetic nervous system in diabetics who do not manifest symptoms or signs referable to autonomic system dysfunction.     

脑梗死患者交感神经皮肤反应的临床研究

目的 :应用交感神经皮肤反应检查法 (SSR)定量评价脑梗死患者的交感神经反射活动 ,并探讨其植物神经中枢调节机制。方法 :对 42例急性期脑梗死患者 ,利用肌电图仪刺激双侧正中神经记录SSR ,并以 30例健康人作对照组进行研究。结果 :脑梗死急性期病灶同侧SSR异常 38例 (90 % ) ,对侧为 30例 (71% )。皮层梗死组主要表现为双侧SSR波幅对称性降低 ,与对照组比较差异非常显著 (P <0 0 0 1)。内囊—基底节区梗死组的异常表现形式有SSR缺失 ,双侧波幅降低 (同侧 :P <0 0 0 1,对侧 :P <0 0 1) ,以病灶同侧波幅降低更显著。结论 :SSR可定量评价脑梗死患者的交感神经功能状态 ,对脑梗死患者的植物神经功能障碍有亚临床诊断价值 ;脑梗死急性期可致SSR抑制 ,内囊—基底节区对植物神经系统有重要的调节作用。     

Sympathetic skin responses in patients with hyperthyroidism

BACKGROUND: The aim of this study was to investigate the disorders of sympathetic nervous system in patients with hyperthyroidism using sympathetic skin response (SSR). MATERIAL AND METHODS: Twenty-two newly diagnosed cases with hyperthyroidism were included in the study. The results were compared with those of 20 healthy controls. SSR was recorded with the contralateral electrical stimulation of the median nerve (of the upper extremities) and tibial nerve (of the lower extremities) with active electrodes placed on palms and soles and reference electrodes attached on the dorsal aspects of hands and feet. RESULTS: Ages of the cases with hyperthyroidism and controls ranged between 15-65 years (mean: 46.7 +/- 15.0 years) and 24-62 years (mean: 39.6 +/- 9.8 years) respectively (p > 0.05). In all the control subjects SSR could be obtained, while from the lower extremities of 4 cases with hyperthyroidism (18.0%) SSR could not be elicited. Mean SSR latencies of lower extremities were found significantly longer than control group (p < 0. 05). No difference was detected between mean amplitudes of SSR in upper and lower extremities. CONCLUSION: These findings suggest that SSR is useful for investigation of sympathetic nervous system involvement in cases with hyperthyroidism.     

22例糖尿病合并阳萎患者的交感皮肤反应研究

目的：探讨Ⅱ型糖尿病阳萎患者外阴交感皮肤反应（SSR）与肢体SSR和胫神经运动传导速度（MCV）的相关性,以评价其对糖尿病合并阳萎早期诊断防治及疗效的意义。方法：对22例糖尿病合并阳萎患者进行会阴与肢体SSR以及胫神经MCV检测,并以19例非阳萎糖尿病者和28例正常男性作对照。结果：糖尿病合并阳萎患者肢体和会阴SSR潜伏期较非阳萎糖尿病者和正常对照组明显延长,糖尿病合并阳萎患者肢体和会阴SSR波幅面积较非阳萎糖尿病得和正常对照组明显缩小,结论：糖尿病合并阳萎的患者SSR潜伏期延长,MCV减慢,SSR波幅亦明显缩小;肢体与会阴SSR的潜伏期均可反映糖尿病神经性阳萎患者的植物神经病变。因此检测肢体SSR对于防治糖尿病阳萎有重要的临床应用价值。     

Sympathetic skin response in peritoneal dialysis patients

To determine if there is any difference in nerve conduction studies or sympathetic skin response (SSR) between patients on peritoneal dialysis and those on regular hemodialysis, we did a cross-sectional observational study. The study group consisted of 24 patients on peritoneal dialysis (PD) (12 men, aged 45 +/- 17 years) and 20 patients on hemodialysis (HD) (11 men, aged 50 +/- 22 years). All of these patients were in stable clinical condition, they were receiving adequate dialysis, and none of them had systemic diseases. Motor and sensory nerve conduction studies of the common and medial peroneal nerve and SSR were performed in all patients. There were no differences in motor and sensory nerve conduction velocities between PD and HD patients. All PD patients had detectable SSR. However, six patients on HD (30%) failed to show SSR (p < 0.05). Mean SSR amplitude was higher in PD patients than in HD patients (1233 +/- 843 vs. 605 +/- 771 microv, p < 0.05). There were no differences in mean SSR latency between PD and HD patients. PD modality (continuous ambulatory PD vs. automated PD) or the presence of residual renal function did not influence nerve conduction studies or SSR. In conclusion, using standard nerve conduction studies, no differences could be found between HD and PD. However, a higher proportion of patients on HD showed an impaired SSR, suggesting that subclinical neuropathy may be more common in HD than PD patients.     

交感神经皮肤反应对评价慢性肾功能不全患者植物神经损害的意义

目的:探讨慢性肾功能不全(CRF)患者交感神经皮肤反应(SSR)的变化及其临床意义。方法:对52例CRF患者行SSR检测,并与32例正常对照组比较。结果:CRF组SSR波幅低于正常对照组,潜伏期较对照组延长(P<0.01)。CRF组SSR总异常率为71%,其中上肢异常率为48%,下肢异常率为71%;慢性肾衰早期组16例中7例(44%)SSR异常,慢性肾衰组19例中14例(74%)SSR异常,尿毒症组17例中16例(94%)SSR异常;CRF患者上下肢之间、不同亚组之间SSR异常率比较差异有极显著意义(P<0.01)。CRF组病程和血肌酐水平与SSR潜伏期间的偏相关系数分别为0.4732(P<0.01)和0.3247(P<0.05),而与SSR波幅间的偏相关系数为-0.3173和-0.3062(P均<0.05);年龄与SSR潜伏期偏相关系数为0.0434(P>0.05),与SSR波幅偏相关系数为-0.4445(P<0.01)。结论:SSR的异常反映了CRF患者常合并交感神经损害,且与病程、肾功能损害程度及年龄因素相关,SSR检测可作为评价CRF患者交感神经损害敏感的客观指标。     

Comparison of sympathetic skin response between palmar hyperhidrotic and normal subjects

Palmar hyperhidrosis is a disorder with excessive sweating. The purpose of this study is to evaluate the autonomic function in palmarhyperhidrotic patients with Sympathetic skin response (SSR) test. In this study SSr was performed for the upper limbs of 20 patients with palmar hyperhidrosis, who did not have any other systemic or localized wrist and palmar disease as "Involved Group" and 28 healthy subject as "Control Group" without any palmar hyperhidrosis, systemic or local disease. The findings indicated a significant difference between latency and amplitude of the two groups (P.V. < 0.001) 95%. Beside, in this study, we observed a direct correlation between severity of symptom and the degree of SSR abnormality. Therefore, involvement of sympathetic nervous system in palmar hyperhidrosis were highly suspected.     

Comparison of sympathetic sprouting in sensory ganglia in three animal models of neuropathic pain

Sympathetic postganglionic fibers sprout in the dorsal root ganglion (DRG) after peripheral nerve injury. Therefore, one possible contributing factor of sympathetic dependency of neuropathic pain is the extent of sympathetic sprouting in the DRG after peripheral nerve injury. The present study compared the extent of sympathetic sprouting in the DRG as well as in the injured peripheral nerve in three rat neuropathic pain models: (1) the chronic constriction injury model (CCI); (2) the partial sciatic nerve ligation injury model (PSI); and (3) the segmental spinal nerve ligation injury model (SSI). All three methods of peripheral nerve injury produced behavioral signs of ongoing and evoked pain with some differences in the magnitude of each pain component. The density of sympathetic fibers in the DRG was significantly higher at all examined postoperative times than controls in the SSI model, while it was somewhat higher than controls only at the last examined postoperative time (20 weeks) in the CCI and PSI models. Therefore, data suggest that, although sympathetic changes in the DRG may contribute to neuropathic pain syndromes in the SSI model, other mechanisms seem to be more important in the CCI and PSI models at early times following peripheral nerve injury.     

西酞普兰和文拉法新对抑郁症患者交感皮肤反应的影响

目的探讨不同药理机制的抗抑郁药西酞普兰和文拉法新对抑郁症患者交感皮肤反应（SSR）影响的差异。方法 67例抑郁症患者随机分为西酞普兰和文拉法新组,于治疗前、治疗后4周末测定SSR及汉密尔顿抑郁量表（HAM D 17）,并与35例正常对照组比较。结果①治疗前两患者组SSR潜伏期均高于对照组、波幅均低于对照组（LSD检验,P均=0.000）;治疗后,两患者组潜伏期降低（t=3.616,5.457;P=0.001,0.000）、波幅提高（t=-3.134,-6.067;P=0.004,0.000）,与对照组相比差异均有统计学意义（LSD检验,P均=0.000）;②治疗后文拉法新组SSR潜伏期变化率高于西酞普兰组（F=4.379,P=0.040）;③患者HAM D总分与SSR潜伏期呈正相关（r=0.359,P=0.003）、与波幅呈负相关（r=-0.282,P=0.021）。结论抑郁症患者SSR潜伏期异常增高、波幅异常降低,提示存在自主神经功能异常,抗抑郁药能降低SSR潜伏期、提高波幅,文拉法新的作用优于西酞普兰。     

32例糖尿病患者交感神经皮肤反应的探讨

目的 :应用交感神经皮肤反应 (SSR)探讨与糖尿病 (DM)相关的植物神经功能状况。方法 :对 32例DM患者及正常组采用电刺激法进行SSR检测。结果 :正常组SSR波形可分为三种类型 :P型、N型、M型 ,其中M型易产生适应性 ,受皮温、刺激强度、深呼吸等影响。 32例DM患者SSR潜伏期异常 17例 ,异常率为 5 3%。DM组与正常组的SSR相比 ,潜伏期和波幅的差异均有非常显著性意义 (P <0 0 1)。病程≤ 5年DM组与正常组的SSR相比 ,潜伏期和波幅的差异均有显著性意义 (P <0 0 5 ) ;而与病程 >5年DM组相比 ,仅潜伏期差异显示显著性意义 (P <0 0 5 ) ,波幅虽有降低 ,但无统计学差异。结论 :SSR可以评价DM患者的植物神经功能状况 ,尤其是潜伏期更有价值 ,可以作为一项动态观察指标。     

皮肤交感反应对糖尿病自主神经病的诊断价值

目的：探讨皮肤交感反应（SSR）检查对诊断糖尿病自主神经病的价值。方法：将122例2型糖尿病患者分为有自主神经症状组（71例）和无自主神经症状组（51例）,每位患者进行神经传导检查及SSR检查。分析比较两组患者SSR与神经传导检查结果的差异。结果：两组间SSR、神经传导的检查结果比较差异无统计学意义（P〉0．05）。43例SSR正常的患者中有29例（65．9％）有自主神经症状,22例（51。2％）病程短于5年;79例SSR异常的患者中有43例（54．4％）有自主神经症状,37例（46．8％）糖化血红蛋白（HbA1C）高于8．5％。结论：SSR与自主神经症状无明显相关性;糖尿病控制情况及病程对SSR结果均有影响。     

巴金森病与多系统萎缩患者的交感神经皮肤反应研究

目的：研究原发性巴金森病（IPD）与多系统萎缩（MSA）交感神经皮肤反应（SSR）,以探讨它们自主神经功能障碍的差异。方法：对31例IPD、17例MSA和83位正常人的SSR结果比较,分析PD组和MSA组SSR异常特征和与病程、自主神经症状的相关性。结果：MSA组SSR异常率（76％）显著高于IPD组（45％）,以双侧异常多见。3年内病程的SSR异常率为73％,并与自主神经症状相关。IPD组SSR异常与病程显著相关,与自主神经症状无完全对应关系,SSR异常更多见于震颤侧。结论：MSA广泛而严重的自主神经系统受累可能是SSR异常显著有别于IPD的基础。SSR异常出现早,呈双侧改变,且与自主神经症状有对应关系,则更多提示MSA的可能。     

Segmental organization of visceral and somatic input onto C3-T6 spinothalamic tract cells of the monkey.

1. Referred pain of visceral origin has three major characteristics: visceral pain is referred to somatic areas that are innervated from the same spinal segments as the diseased organ; visceral pain is referred to proximal body regions and not to distal body areas; and visceral pain is felt as deep pain and not as cutaneous pain. The neurophysiological basis for these phenomena is poorly understood. The purpose of this study was to examine the organization of viscerosomatic response characteristics of spinothalamic tract (STT) neurons in the rostral spinal cord. Interactions were determined among the following: 1) segmental location, 2) effects of input by cardiopulmonary sympathetic, greater splanchnic, lumbar sympathetic, and urinary bladder afferent fibers, 3) location of excitatory somatic field, e.g., hand, forearm, proximal arm, or chest, 4) magnitude of response to hair, skin, and deep mechanoreceptor afferent input, and 5) regional specificity of thalamic projection sites. 2. A total of 89 STT neurons in segments C3-T6 were characterized for responses to visceral and somatic stimuli. Neurons were activated antidromically from the contralateral ventroposterolateral oralis or caudalis nuclei of the thalamus. Cell responses to visceral and somatic stimuli were not different on the basis of the thalamic site of antidromic activation. Recording sites for 61 neurons were located histologically; 87% of lesion sites were located in laminae IV-VII or X. There was no relationship between response properties of the neurons and spinal laminar location. 3. Different responses to visceral stimuli were observed in three zones of the rostral spinal cord: C3-C6, C7-C8, and T1-T6. In C3-C6, urinary bladder distension (UBD) and electrical stimulation of greater splanchnic and lumbar sympathetic afferent fibers inhibited STT cells. Electrical stimulation of cardiopulmonary sympathetic afferents increased cell activity in C5 and C6 and either excited or inhibited STT cells in C3 and C4. In the cervical enlargement (C7-C8), STT cells generally were either inhibited or showed little response to stimulation of visceral afferent fibers. In T1-T6, input from greater splanchnic and cardiopulmonary sympathetic afferent nerves increased activity of STT cells. Lumbar sympathetic afferent input inhibited cells in T1-T2 and had little effect on cells in T3-T6, whereas UBD decreased cell activity in all segments studied. 4. In general, stimulation of somatic structures increased activity of STT neurons in segments that received primary afferent innervation from the excitatory somatic receptive field or in the segments immediately adjacent to these segments. Only input from the forelimb, especially the hand, markedly excited cells in C7 and C8.+     

加巴喷丁对脊神经结扎大鼠背根神经节交感神经芽生的影响

目的:观察加巴喷丁干预后疼痛大鼠痛阈变化及背根神经节(DRGs)中交感神经芽生的改变。方法:将SD雄性大鼠随机分为正常对照组、模型组和加巴喷丁组,于术前及术后5 d每天检测大鼠痛阈变化;术后5 d取各组大鼠手术侧腰5和腰4及对侧腰5 DRG,观察DRGs中交感纤维数量及篮状结构的变化。结果:加巴喷丁可以显著抑制脊神经结扎引起的痛觉过敏;模型组(手术侧腰5及腰4)表现为交感神经节后纤维的异常增生,加巴喷丁干预后,手术侧腰5和腰4 DRGs TH-IR纤维及篮状结构的数量明显低于模型组。结论:加巴喷丁能提高疼痛大鼠痛阈,其机制可能是通过降低脊髓DRG中交感神经的芽生而产生镇痛作用。     

Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer pain

For many patients, pain is the first sign of cancer and, while pain can be present at any time, the frequency and intensity of pain tend to increase with advancing stages of the disease. Thus, between 75 and 90% of patients with metastatic or advanced-stage cancer will experience significant cancer-induced pain. One major unanswered question is why cancer pain increases and frequently becomes more difficult to fully control with disease progression. To gain insight into this question we used a mouse model of bone cancer pain to demonstrate that as tumor growth progresses within bone, tropomyosin receptor kinase A (TrkA)-expressing sensory and sympathetic nerve fibers undergo profuse sprouting and form neuroma-like structures. To address what is driving the pathological nerve reorganization we administered an antibody to nerve growth factor (anti-NGF). Early sustained administration of anti-NGF, whose cognate receptor is TrkA, blocks the pathological sprouting of sensory and sympathetic nerve fibers, the formation of neuroma-like structures, and inhibits the development of cancer pain. These results suggest that cancer cells and their associated stromal cells release nerve growth factor (NGF), which induces a pathological remodeling of sensory and sympathetic nerve fibers. This pathological remodeling of the peripheral nervous system then participates in driving cancer pain. Similar to therapies that target the cancer itself, the data presented here suggest that, the earlier therapies blocking this pathological nerve remodeling are initiated, the more effective the control of cancer pain.     

A quantitative analysis of the sensory and sympathetic innervation of the mouse pancreas

Pain from pancreatitis or pancreatic cancer can be both chronic and severe although little is known about the mechanisms that generate and maintain this pain. To define the peripheral sensory and sympathetic fibers involved in transmitting and modulating pancreatic pain, immunohistochemistry and confocal microscopy were used to examine the sensory and sympathetic innervation of the head, body and tail of the normal mouse pancreas. Myelinated sensory fibers were labeled with an antibody raised against 200 kD neurofilament H (clone RT97), thinly myelinated and unmyelinated peptidergic sensory fibers were labeled with antibodies raised against calcitonin gene-related peptide (CGRP) and post-ganglionic sympathetic fibers were labeled with an antibody raised against tyrosine hydroxylase (TH). RT97, CGRP, and TH immunoreactive fibers were present in parenchyma of the head, body and tail of the pancreas with the relative density of both RT97 and CGRP expressing fibers being head>body>tail, whereas for TH, a relatively even distribution was observed. In all three regions of the pancreas, RT97 fibers were associated mainly with large blood vessels, the CGRP fibers were associated with the large- and medium-sized blood vessels and the TH were associated with the large- and medium-sized blood vessels as well as capillaries. In addition to this extensive set of sensory and sympathetic nerve fibers that terminate in the pancreas, there were large bundles of en passant nerve fibers in the dorsal region of the pancreas that expressed RT97 or CGRP and were associated with the superior mesenteric plexus. These data suggest the pancreas receives a significant sensory and sympathetic innervation. Understanding the factors and disease states that sensitize and/or directly excite the nerve fibers that terminate in the pancreas as well as those that are en passant may aid in the development of therapies that more effectively modulate the pain that frequently accompanies diseases of the pancreas, such as pancreatitis and pancreatic cancer.