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Sympathetic nervous system modulation of the immune system. III. Alterations in T and B cell proliferation and differentiation in vitro following chemical sympathectomy.

Functional changes in lymph node (LN) and spleen lymphocytes were examined following sympathetic denervation of adult mice with 6-hydroxydopamine (6-OHDA). Sympathectomy reduced in vitro proliferation to concanavalin A (ConA) by LN cells and decreased LN Thy-1+ and CD4+ T cells. At the same time, ConA-induced interferon-gamma (IFN-gamma) production was increased, but interleukin-2 (IL-2) production was not altered. After sympathectomy, lipopolysaccharide (LPS)-stimulated proliferation of LN B cells was enhanced, in parallel with an increase in the proportion of sIgM+ cells. LPS-induced polyclonal IgM secretion was decreased, whereas polyclonal IgG secretion was dramatically enhanced. In the spleen, ConA and LPS responsiveness was reduced after sympathectomy, as was IL-2 and IFN-gamma production. The decreased proliferation was not associated with changes in splenic T and B cell populations. The uptake blocker desipramine prevented the 6-OHDA-induced changes in spleen and LN, indicating that these alterations were dependent upon neuronal destruction. These results provide evidence for heterogeneity of sympathetic nervous system regulation of T and B lymphocyte function and for organ-specific influences on immune function.

Animals↗

Endoscopic transthoracic sympathectomy: an efficient and safe method for the treatment of hyperhidrosis.

BACKGROUND: Hyperhidrosis of the palms, axillae, and face has a strong negative impact on the quality of life for many persons. Existing nonsurgical therapeutic options are far from ideal. Definitive cure can be obtained by upper thoracic sympathectomy. The traditional open surgical technique is a major procedure; few patients and doctors have found that risk-benefit considerations favor surgery. Endoscopic minimal invasive surgical techniques are now available. OBJECTIVE: We investigated whether endoscopic ablation of the upper thoracic sympathetic chain is efficient and safe in the treatment of hyperhidrosis. METHODS: We treated 850 patients with bilateral endoscopic transthoracic sympathectomy. RESULTS: There was no mortality or life-threatening complication. Nine patients (1%) required intercostal drainage because of hemothorax or pneumothorax. Treatment failure occurred in 18 cases (2%) and symptoms recurred in 17 patients (2%). At the end of follow-up (median, 31 months) 98% of the patients reported satisfactory results. CONCLUSION: Endoscopic transthoracic sympathectomy is an efficient, safe, and minimally invasive surgical method for the treatment of palmar, axillary, and facial hyperhidrosis.

Adolescent↗

Increase of dopamine beta-hydroxylase immunoreactivity in non-noradrenergic nerves of rat cerebral arteries following long-term sympathectomy.

The expression of dopamine beta-hydroxylase (DBH) and tyrosine hydroxylase (TH) immunoreactivity (IR) after short-term (2 days) and long-term (3 weeks) sympathectomy was investigated in rat cerebral vessels, dura mater and pterygopalatine ganglion neurones (which are known to project to cerebral arteries) by immunohistochemistry at both the light and electron microscopical levels. TH-IR, like glyoxylic acid-induced fluorescence, was completely abolished by sympathectomy. By contrast, DBH-IR was localized in nerve fibres, lacking 5-hydroxydopamine (5-OHDA)-labelled vesicles, along cerebral vessels of long-term sympathectomized rats, but not in the dura mater, and in pterygopalatine ganglia, where the number of DBH-IR neurons increased from 27.87% to 54.11%. Since virtually all the pterygopalatine neurons displayed choline acetyltransferase (ChAT)-IR, both in control and sympathectomized rats, it is concluded that long-term sympathectomy caused an increase of the expression of DBH-IR in cholinergic neurones of the pterygopalatine ganglion, without these neurons producing or storing noradrenaline.

Animals↗

Effects of sympathectomy on the cutaneous temperature abnormalities in rats with chronic constriction injury of the sciatic nerve.

Effects of surgical sympathectomy on the cutaneous temperature abnormalities of plantar surface evoked by the chronic constriction injury (CCI) of the sciatic nerve were investigated in the rat. In normal animals, there were very small temperature differences between both plantar surfaces. There were also very small temperature differences in plantar surfaces following the sympathectomy prior to CCI. In rats with CCI, the cutaneous temperature of the nerve-injured plantar surface was significantly higher (warmer) than that of the contralateral plantar surface during the first week following CCI, and then became lower (cooler). Surgical sympathectomy prior to and just after CCI significant suppressed the temperature abnormalities during the first week, but no effect was observed after 2 weeks following CCI. These observations indicate that sympathetic vasoconstriction may contribute to the cutaneous temperature abnormalities evoked by CCI during the early stage, but does not affect the abnormalities at later stages.

Animals↗

Sympathectomy induces c-Jun in adult trigeminal neurons: an immunohistochemical and tract-tracing study.

The induction of the immediate early gene product c-Jun was investigated in trigeminal ganglia following surgical removal of the superior cervical ganglion (SCG). A 5-fold increase in c-Jun-immunoreactive neurons was detected by 48 h post-surgery in ipsilateral trigeminal ganglia of sympathectomized rats. This increase persisted for 6 days. When examined 4 months after sympathectomy, c-Jun expression had returned to basal levels. The possibility that trigeminal neurons project to the SCG, and therefore induce c-Jun by being axotomized by sympathectomy, was also examined using retrograde fluorescent tracing. A very limited number of trigeminal neurons were retrogradely labeled from the SCG. These data indicate that c-Jun induction occurs in sensory neurons following perturbations to sympathetic ganglia, and that trigeminal neurons may project to the SCG, but that c-Jun induction cannot be ascribed to axotomy following surgical sympathectomy. Thus, these findings support anatomical and functional interconnections between the sensory and autonomic nervous systems. The relationship of c-Jun induction with plasticity phenomena is discussed.

Animals↗

Post-sympathectomy neuralgia: hypotheses on peripheral and central neuronal mechanisms.

Post-sympathectomy neuralgia is proposed here to be a complex neuropathic and central deafferentation/reafferentation syndrome dependent on: (a) the transection, during sympathectomy, of paraspinal somatic and visceral afferent axons within the sympathetic trunk; (b) the subsequent cell death of many of the axotomized afferent neurons, resulting in central deafferentation; and (c) the persistent sensitization of spinal nociceptive neurons by painful conditions present prior to sympathectomy. Viscerosomatic convergence, collateral sprouting of afferents, and mechanisms associated with sympathetically maintained pain are all proposed to be important to the development of the syndrome.

Animals↗

Reflex sympathetic dystrophy: skin blood flow, sympathetic vasoconstrictor reflexes and pain before and after surgical sympathectomy.

To examine the pathophysiological mechanisms of vascular disturbances and to assess the role of the sympathetic nervous system, 12 patients with reflex sympathetic dystrophy (RSD) of the hand were studied using laser Doppler flowmetry. Cutaneous blood flow, skin resistance and skin temperature were measured at the affected and contralateral hands. Sympathetic vasoconstrictor reflexes were induced bilaterally by deep inspiration. Four patients were treated with unilateral surgical sympathectomy and pain and vascular changes were documented in follow-up investigations. (1) After acclimatization in cold environment (< or = 18 degrees C) blood flow and skin temperature were considerably lower on the affected side in 10 patients. No additional vasoconstrictor reflexes could be elicited. (2) After acclimatization in warm environment (22-24 degrees C) blood flow and skin temperature demonstrated no side differences in all cases. Vasoconstrictor responses were the same on both sides. (3) After sympathectomy vasoconstrictor reflexes were absent. Skin resistance was considerably higher on the affected side. In the first 4 weeks the affected hand was warmer and blood flow was higher compared with the healthy side. Thereafter, skin temperature and perfusion slowly decreased and the affected hand turned from warm to cold. Very regular high amplitude vasomotion waves occurred unilaterally. There were no signs of reinnervation. Two patients had long-term pain relief. We conclude as follows. (1) Side differences in skin temperature and blood flow are no static descriptors in RSD. They are dynamic values depending critically on environmental temperature. Therefore, they have to be interpreted with care when defining reliable diagnostic criteria. (2) Vascular disturbances in RSD are not due to constant overactivity of sympathetic vasoconstrictor neurons. Changes in vascular sensitivity to cold temperature and circulating catecholamines may be responsible for vascular abnormalities. Alternatively, RSD may be associated with an abnormal (side different) reflex pattern of sympathetic vasoconstrictor neurons due to thermoregulatory and emotional stimuli generated in the central nervous system. (3) After sympathectomy, denervation supersensitivity of blood vessels and intense vasomotion may be associated with recurrence of pain in some patients.

Adult↗

Marked increases in calcitonin gene-related peptide-containing nerves in the developing rat following long-term sympathectomy with guanethidine.

Changes in the innervation of the cardiovascular system, urinogenital tract and sympathetic and non-sympathetic ganglia have been examined following long-term sympathectomy. Patterns of innervation were investigated using histochemical and immunohistochemical techniques, while levels of noradrenaline and neuropeptides were measured by neurochemical assays. Large doses of guanethidine (50 mg/kg) were given daily for 3 weeks to 8-day-old rat pups, which were killed at 6 or 20 weeks of age. In both age groups noradrenergic nerves were severely depleted or absent, while in some regions dramatic increases of calcitonin gene-related peptide levels were demonstrated. This was revealed by an increase in the density of nerve fibres and in calcitonin gene-related peptide content (up to 18-fold), most notably in the right atrium and superior cervical ganglion. No changes in substance P- or vasoactive intestinal polypeptide-immunolabelled nerves were seen. Conversely, short-term sympathectomy by 6-hydroxy-dopamine treatment caused a depletion of noradrenaline which was not accompanied by an increase in the number or content of calcitonin gene-related peptide-immunolabelled nerves. The possibility that nerve growth factor is involved in the mechanism of hyperinnervation by calcitonin gene-related peptide-containing sensory nerves following long-term sympathectomy is discussed.

Adrenergic Fibers↗

Thoracoscopic sympathectomy for hyperhidrosis: indications and results.

BACKGROUND: Hyperhidrosis can cause significant professional and social handicaps. Although treatments such as oral medication, botox, and iontophoresis are available, surgical sympathectomy is being increasingly utilized. METHODS: Between January 1997 and December 2002, 180 patients with palmar, axillary, facial, or plantar hyperhidrosis underwent a thoracoscopic sympathectomy. Surgical technique evolved during our study period and included excision of the sympathetic ganglia at T(2), T(3), or T(4) depending on the location of the sweating using monopolar cautery. RESULTS: Patient demographics included 33% males (59/180) and 67% females (121/180), with a mean age of 29.2 years old (range 12 to 76 years old). Ethnic origin was 67% white (122/180), 19% Asian (34/180), 8% Black (14/180), and 6% Hispanic (10/180). Positive family history of hyperhidrosis was noted in 57%. Preoperatively, 49% patients (86/180) had palmar sweating only, 7% patients (12/180) axillary only, 24% patients (43/180) palmar and axillary, 16% patients (28/180) face/scalp only, and 7% patients (11/180) all of the above; additionally 69% patients (125/180) had plantar hyperhidrosis. All procedures were performed through 3-mm and 5-mm ports, and 98% (177/180) were completed as an outpatient procedure. Complications included a mild temporary Horner's Syndrome (n = 1; 0.5%), air leak requiring chest drainage (n = 9; 5%), and bleeding (n = 3; 1.6%) requiring thoracoscopic reexploration (n = 1) and chest drainage (n = 2). Success rates were palmar 100% (109/109), axillary 98% (48/49), and face/scalp 93% (26/28). Plantar hyperhidrosis responded with improvement in 82% (72/88) of all patients. Seventy-eight percent patients (96/123) experienced compensatory hyperhidrosis, usually affecting the stomach, chest, back, and neck. Overall satisfaction was 94% (139/148). CONCLUSIONS: Thoracoscopic sympathectomy is a safe and effective outpatient method for managing hyperhidrosis. Although overall satisfaction is high, patients should be fully informed about the potential for compensatory sweating.

Adolescent↗

Long-term results of thoracoscopic sympathectomy for hyperhidrosis.

BACKGROUND: Thoracoscopic sympathectomy is now the reference treatment for severe palmar hyperhidrosis, but this is offset by the occurrence of compensatory sweating. It has been studied in this series to improve the indications and information given to patients. METHODS: A retrospective review of 124 patients who were previously afflicted with bilateral thoracoscopic sympathectomy 6 years earlier was conducted. Patients were interviewed by postal questionnaire regarding the results and side effects. RESULTS: The series consisted of 89 females (72%) and 35 males and the mean age was 28 years. The main indication was palmo-plantar hyperhidrosis (34%). The mean operating time was 36 minutes and there were no intraoperative complications. Postoperative pneumothorax occurred in 9 patients and 3 patients required a chest drain. The hospital stay was 36 hours for 87.6% of the patients. Postoperative pain occurred in 78% of the patients. Neurologic complications (Horner syndrome, radial paralysis, and dysesthesia of the arm) occurred in 3 patients and disappeared after 2-6 months. Two patients required single-side reoperation because of failure with the first intervention. Eighty-nine replies to questionnaires were received (72%). The results for hands were favorable in 98% and in 63% for axillae. Compensatory sweating occurred in 87% of the patients (serious in 36% and incapacitating in 6%). Despite this 90% of the patients were satisfied or very satisfied. CONCLUSIONS: This study confirms that thoracoscopic sympathectomy is a suitable method of treatment for severe palmar hyperhidrosis but emphasizes the need to offer the patient more informative information, especially regarding compensatory sweating which seems inescapable.

Adult↗

Awake one stage bilateral thoracoscopic sympathectomy for palmar hyperhidrosis: a safe outpatient procedure.

OBJECTIVE: To verify the feasibility and compare the results of thoracoscopic sympathectomy under local anaesthesia (LA) and spontaneous breathing vs. general anaesthesia (GA) with one-lung ventilation. METHODS: Two groups of consecutive patients underwent one stage bilateral T2-T3 thoracoscopic sympathectomy under LA (n=15) and GA (n=30) by the same surgical team for treatment of primary palmar hyperhidrosis. The groups were homogeneous for relevant demographic, physiological and clinical data, including pulmonary function. In both groups, patient's satisfaction was evaluated 24h after surgery by a simple interview and scored into five grades (1=very poor to 5=excellent), while quality of life (QOL) was evaluated by SF-36 and Nottingham's Health Profile questionnaires before and 6 months after surgery. A cost comparison between groups concerning devices, drugs, global in operating room time, medical personnel and hospital stay was also carried out. RESULTS: No operative mortality was recorded. The overall in operating room time for the whole bilateral procedure under LA was 63.55+/-10.58 vs. 86.05+/-5.75 under GA (P<0.01) and temperature increased in all patients from a baseline of 25.42+/-0.56 up to 32.15+/-0.84 degrees C. All patients undergone LA were discharged the same day after a chest roentgenogram and a short stay in the outpatient clinic. Among them three patients (20%) experienced a minimal (<30%) pneumothorax that required no treatment, while five (33.3%) had a trunk compensatory sweating that spontaneously resolved on the long run. Patients undergoing GA were discharged after a mean stay of 1.38+/-0.6 days. Among these, eight (26.6%) had prolonged trunk compensatory sweating that did not persist longer than 3 months. At a follow-up of 7.16+/-2.97 months, QOL was significantly improved with no difference between groups. The overall rate of satisfaction was greater in the LA group (P<0.05). CONCLUSIONS: In our study, awake one stage bilateral thoracoscopic sympathectomy for palmar hyperhidrosis could be safely and effectively performed as an outpatient procedure in patients refusing GA. Postoperative quality of life was equal to that in patients undergone the same procedure under GA, while patient satisfaction was better and cost were significantly reduced.

Adult↗

Upper dorsal endoscopic thoracic sympathectomy: a comparison of one- and two-port ablation techniques.

OBJECTIVE: Facial blushing and hyperhidrosis, particularly in the facial, axillary or palmar distribution, are socially, professionally, and psychologically debilitating conditions. Endoscopic thoracic sympathectomy can be carried out through multiple ports or by using a single port and a modified thoracoscope with integrated electrocautery. We reviewed our own experience to compare outcomes between these methods. METHODS: One hundred and nine consecutive endoscopic thoracic sympathectomies performed on 96 patients (M:F, 30:66) were examined with respect to operative method, symptom control, and patient satisfaction. Complete follow-up was available on 144 treated sides in 77 patients (80.2%), 38 treated with two ports, 39 performed by a one-port procedure. Mean age was 32.6 years (range 18-63) with a median follow-up of 25 months (range 5-85). Pooled data showed that the mean duration hospital stay was 1.6 nights with no deaths, conversions, or neurological injuries. RESULTS: The one-port group showed superior outcomes in terms of hospital stay, rate of postoperative pneumothorax, and the need for chest drain insertion; however, there was no correlation between number of ports and patient satisfaction. The mean overall satisfaction rating out of 5 was 3.3 with 76.6% of patients rating the outcome as 3 or more. 90.9% had an initial improvement in symptoms, although 21 patients (27.3%) described a late return of symptoms. CONCLUSION: Endoscopic thoracic sympathectomy can be safely and effectively carried out using a single port with similar results to the traditional two-port procedure. The one-port procedure may allow for a shorter duration of stay and lower complication rate.

Adolescent↗

Long-term pulmonary function after thoracic sympathectomy.

BACKGROUND: The purpose of this study was to evaluate the long-term and midterm effects of thoracic sympathectomy on pulmonary function and to assess the influence of the sympathetic nervous system on bronchomotor tone. METHODS: Thirty-seven consecutive patients were diagnosed with primary hyperhidrosis requiring thoracic sympathectomy and were included in this study. Spirometry and methacholine challenge testing were performed before and 3 months after surgery. To assess the long-term effects of the intervention, another spirometric study was performed 1 year later. RESULTS: Spirometry 3 months after surgery showed a significant decrease in the forced vital capacity (-5.2%), the forced expiratory volume in the first second (-6.1%), and the forced expiratory flow between 25% and 75% of vital capacity (-5.1%). Whereas methacholine challenge testing before surgery was positive in 3 subjects (2 of whom were asthmatic), it was positive in 6 patients after the procedure; differences were not statistically significant. After 12 months, forced vital capacity started recovering, and forced expiratory volume in the first second and forced expiratory flow rate 25% to 75% showed a sustained and significant reduction (-2.8% and -11.2%, respectively); however, patients remained asymptomatic. CONCLUSIONS: We conclude that thoracic sympathectomy generates a mild, although significant, impairment of the bronchomotor tone, with no clinical consequences. These results suggest that the sympathetic nervous system is involved in pulmonary bronchomotor tone.

Adolescent↗

Influence of sympathectomy in humans on the rhythmicity of 6-sulphatoxymelatonin urinary excretion.

The amount of 6-sulphatoxymelatonin, the chief metabolite of melatonin, in the urine was measured in nine patients, who were subjected to bilateral sympathectomy at the second thoracic ganglionic level for treatment of hyperhidrosis of the palms. All patients showed before surgery a normal 6-sulphatoxymelatonin excretion with a peak in the excretion during the night time. After the sympathectomy, the high night time excretion was clearly abolished in five patients but remained high in four patients. This indicates that the segmental locations of the preganglionic sympathetic perikarya in the spinal cord, stimulating the melatonin secretion in the pineal gland in humans, vary between individuals. An increase in daytime melatonin excretion was observed in the patients responding to the sympathectomy with an abolished 6-sulphatoxymelatonin rhythm. This increase could indicate that the final sympathetic neurons innervating the pineal gland might have a both stimulatory and inhibitory function.

Adult↗

Immunoglobulin producing cells in the rat dental pulp after unilateral sympathectomy.

Recent studies show that sympathetic nerves participate in immunomodulation. We investigated the effects of unilateral sympathectomy on recruitment of cells expressing kappa and lambda (kappa and lambda) light chains in the rat dental pulp. Superior cervical ganglion was removed in experimental rats (n=10) while control rats (n=8) received sham surgery. Following perfusion 18 days later, mandibular jaws were processed for immunohistochemistry and electron microscopy. Sympathectomy results in recruitment of cells expressing kappa and lambda light chains into the dental pulp (P=0.005). Electron microscopy revealed these cells to be mainly plasma cells and Mott cells. We conclude that neural imbalance caused by unilateral sympathectomy recruits immunoglobulin producing cells in the dental pulp. Our results are in agreement with a model of immune regulation in which the sympathetic nervous system exerts a tonic regulatory effect over lymphocyte proliferation and migration.

Animals↗

Laser Doppler scanning study of palmar skin perfusion for patients with hyperhidrosis before and after thoracic sympathectomy.

BACKGROUND: Palmar hyperhidrosis is effectively treated by thoracic sympathectomy. Previous reports revealed that palmar skin temperature and perfusion increased on focal palmar regions after treatment. This study aimed to investigate the blood flow change over the whole palmar surface after the procedure. METHODS: Thirty patients with severe palmar hyperhidrosis were included for study. Each participant received measurement of palmar skin perfusion by a laser Doppler image scanner 1 day before and 1 day after surgery. Concomitantly, palmar skin temperature was recorded by a contact thermometer probe. One patient underwent intraoperative recording of palmar skin perfusion. RESULTS: Palmar skin perfusion and temperature increased significantly after thoracic sympathectomy. Intraoperative measurement performed for a patient showed a similar trend of increment of palmar skin blood flow. CONCLUSIONS: The global skin perfusion of palms can be analyzed in real time by the laser Doppler image scanner. This technique could be useful for analysis of blood flow changes in other body surface regions after thoracic sympathectomy.

Adolescent↗

Thoracoscopic sympathectomy for upper limb hyperhidrosis: looking for the right operation.

BACKGROUND: Thoracoscopic sympathectomy is the most effective treatment for upper limb hyperhidrosis. However, this is offset by the occurrence of a high rate of side effects, such as embarrassing compensatory sweating. Anticipating that a technique that respects the sympathetic chain and divides only the rami communicantes may lead to fewer side effects, we assessed the technique described by R. Wittmoser, comparing it with conventional thoracoscopic sympathecomy. METHODS: A total of 240 thoracoscopic sympathectomies were performed in 124 patients suffering from upper limb hyperhidrosis. Fifty-four patients underwent a conventional sympathectomy (group TS), 62 underwent division of the rami communicantes with respect to the main trunk (group SS), and 8 underwent both procedures (group TS/SS) because of accidental division of the chain during dissection. The mean follow-up is 8 months. RESULTS: No recurrence was observed in group TS whereas six (5%) occurred in group SS (p < 0.05). The global rate of compensatory sweating was about the same in both groups: 72.2% in group TS and 70.9% in group SS. However, the rate of embarrassing or disabling compensatory sweating was significantly higher in group TS (50%) than in group SS (21%) (p < 0.001). CONCLUSIONS: Although selective division of the rami communicantes results in a significant decrease in the rate of disturbing side effects, it also leads to recurrences that are usually not observed at that level in patients treated with the conventional technique. Therefore other means of achieving the ideal operation should be explored, that is, a technique associated with a high success rate but a minimal number of side effects.

Adolescent↗

The effects of sympathectomy on capsaicin-evoked fos expression of spinal dorsal horn GABAergic neurons.

Electrophysiological studies have suggested that activity of spinal GABAergic interneurons can be enhanced following intradermal injection of capsaicin (CAP). This activity is proposed to be involved in the generation of dorsal root reflexes (DRRs) that contribute to neurogenic inflammation. We have recently reported that NMDA or non-NMDA antagonists by intrathecal pretreatment attenuate the increased Fos expression in spinal dorsal horn GABAergic neurons after intradermal injection of CAP in rats. Sympathetic efferents have been suggested to modulate inflammatory pain possibly by interactions with primary afferent terminals. In electrophysiological studies by our group, enhancement of the CAP-induced DRRs could be prevented by surgical sympathectomy and blocked by intraarterial pretreatment of the foot with alpha(1)- but not by alpha(2)-adrenoceptor antagonists. In order to determine morphologically if surgical sympathectomy changes the expression of Fos in GABAergic neurons in the lumbosacral spinal cord induced by CAP injection, further experiments were performed using immunofluorescence double-labeling staining at 30 min following CAP or vehicle injection into the glabrous skin of one hind paw of anesthetized rats both in sham-operated and sympathectomized animals. Our results showed that the proportion of Fos-positive GABAergic neuronal profiles was significantly increased following CAP injection (48.8+/-4.76%) compared to vehicle injection (23.8+/-5.1%) in laminae I-V on the ipsilateral side (P<0.05). However, when sympathetic efferents were removed surgically 7-10 days prior to the experiment (n=6), only 32.07+/-9.03% of GABA-immunoreactive neuronal profiles were stained for Fos following CAP injection, a significant reduction in the CAP-evoked Fos-staining of GABAergic neurons after surgical sympathectomy. These findings support our previous electrophysiological studies that GABAergic neurons take part in nociceptive processing within the spinal dorsal horn and suggest that sympathetic efferents may affect nociceptive transduction in the periphery.

Animals↗