Substance-P-induced protein extravasation is bilaterally increased in complex regional pain syndrome

Pain, mechanical hyperalgesia, edema, increased skin temperature, and skin reddening are characteristic symptoms of acute complex regional pain syndrome (CRPS). We have recently demonstrated facilitated neurogenic inflammation on the affected limb. To further elucidate the underlying mechanisms, exogenous substance P (SP) in ascending concentrations (10(-9), 10(-8), 10(-7), 10(-6) M) was intradermally applied to the affected and the unaffected limbs, respectively, in two groups of 11 CRPS patients each using the microdialysis technique. Fourteen healthy volunteers served as controls for SP application, and 9 volunteers and 10 patients served as controls for saline perfusion. Dialysate protein content was measured photometrically to assess plasma protein extravasation. Significant differences in dialysate protein content were found after 10(-9) M SP (affected side, 98.4 +/- 8.4% of baseline value; unaffected side, 104.4 +/- 5.6%; controls, 70.7 +/- 4.1%; P < 0.005) and after 10(-6) M SP (affected, 169.7 +/- 24.2%; unaffected, 189.4 +/- 19.1%; controls, 122.2 +/- 12.0%; P < 0.05). While 10(-9) M SP induced no protein extravasation in controls, it provoked protein extravasation in 6 of 11 patients on the affected and in 5 of 11 patients on the unaffected side (P < 0.01). We conclude that SP-induced plasma protein extravasation is increased in CRPS patients on both the affected and unaffected limbs. The underlying mechanism might be impaired SP inactivation. Thus, our results further support the hypothesis that neurogenic inflammation plays an important role in the initiation of CRPS.     

Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post‐ischemic pain model of complex regional pain syndrome type I in rats

Complex regional pain syndrome type 1 (CRPS‐I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post‐ischemia pain (CPIP) as a model of CRPS‐I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS‐I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS‐I in the setting of ischemia and reperfusion injury.     

Cutaneous vascular responses evoked by noxious stimulation in rats with the spinal nerve ligation-induced model of neuropathy

Antidromic activation of nociceptive nerve fibres innervating the skin produces an axon reflex that involves extravasation and vasodilation of cutaneous blood vessels. We determined whether the axon reflex of the hindlimb skin is influenced by an experimental model of neuropathy induced by unilateral ligation of spinal nerves L(5) and L(6) in the rat. Ligation of spinal nerves induced symptoms mimicking tactile allodynia, as indicated by a marked decrease of the hindlimb withdrawal threshold to mechanical stimulation. The axon reflex induced by antidromic electrical stimulation of nociceptive fibres innervating the plantar skin ipsilateral to the ligation was attenuated according to determination of extravasation response and blood flow response. Lidocaine block or transection of the sciatic nerve of the neuropathic limb did not induce any change in basal blood flow of the plantar skin. The results indicate that ligation of spinal nerves induces an attenuation of the axon reflex. This attenuation reflects a decrease in the efferent function of primary afferent nociceptors innervating the hypersensitive skin of the hindpaw. The attenuation of antidromically-induced vascular responses was not caused by overriding sympathetic activity, as indicated by lack of blood flow effects by lidocaine blocks or a transection of the sciatic nerve.     

The important role of neuropeptides in complex regional pain syndrome.

OBJECTIVE: To test the contribution of neurogenic inflammation and neuropeptide release to the pathophysiology of complex regional pain syndrome (CRPS). BACKGROUND: CRPS is characterized by edema and increased skin temperature, sympathetic dysfunction and pain, or hyperalgesia. This investigation was prompted by a recent study by the authors that suggested a facilitated neurogenic inflammation in CRPS. METHODS: In addition to physical examination, calcitonin gene-related peptide (CGRP) serum concentrations were measured using a radioimmunoassay (RIA) for human CGRP in 19 patients with acute CRPS, on the affected and unaffected sides (n = 13), before and 9 months after therapy (n = 9). In addition, an age- and sex-matched group of 16 healthy controls was investigated. RESULTS: In blood from the cubital vein, CGRP levels in patients with CRPS (122.2 +/- 14.6 pmol/L) were increased (controls 83.8 +/- 6.7 pmol/L, p < 0.03). There was no difference between the affected and unaffected sides. There was, however, a reduction of serum CGRP after therapy (acute disease: 141.2 +/- 18.5 pmol/L, after therapy 106.7 +/- 11.3 pmol/L, p < 0.005); absolute CGRP levels then no longer differed from controls. Increased serum CGRP was correlated to the incidence of nerve lesions (p < 0.02) and hyperhidrosis (p < 0.04). There was no correlation to other clinical symptoms, duration of CRPS, or pain. However, normalization of CGRP after therapy was accompanied by clinical improvement of local inflammatory signs, but not by pain reduction. CONCLUSIONS: Increased systemic CGRP levels in patients with acute CRPS suggest neurogenic inflammation as a pathophysiologic mechanism contributing to vasodilation, edema, and increased sweating. However, pain and hyperalgesia, in particular in chronic stages, were independent of increased neuropeptide concentration.     

Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small‐fiber neuropathy?

Neurologist S. Weir Mitchell first described “causalgia” following wartime nerve injury, with its persistent distal limb burning pain, swelling, and abnormal skin color, temperature, and sweating. Similar post‐traumatic symptoms were later identified in patients without overt nerve injuries after trauma. This was labeled reflex sympathetic dystrophy (RSD; now complex regional pain syndrome type I [CRPS‐I]). The pathophysiology of symptoms is unknown and treatment options are limited. We propose that persistent RSD/CRPS‐I is a post‐traumatic neuralgia associated with distal degeneration of small‐diameter peripheral axons. Small‐fiber lesions are easily missed on examination and are undetected by standard electrophysiological testing. Most CRPS features—spreading pain and skin hypersensitivity, vasomotor instability, osteopenia, edema, and abnormal sweating—are explicable by small‐fiber dysfunction. Small fibers sense pain and temperature but also regulate tissue function through neuroeffector actions. Indeed, small‐fiber–predominant polyneuropathies cause CRPS‐like abnormalities, and pathological studies of nerves from chronic CRPS‐I patients confirm small‐fiber–predominant pathology. Small distal nerve injuries in rodents reproduce many CRPS features, further supporting this hypothesis. CRPS symptoms likely reflect combined effects of axonal degeneration and plasticity, inappropriate firing and neurosecretion by residual axons, and denervation supersensitivity. The resulting tissue edema, hypoxia, and secondary central nervous system changes can exacerbate symptoms and perpetuate pathology. Restoring the interest of neurologists in RSD/CRPS should improve patient care and broaden our knowledge of small‐fiber functions. Ann Neurol 2009;65:629–638     

Systemic administration of minocycline inhibits formalin-induced inflammatory pain in rat

It has been demonstrated that spinal microglial activation is involved in formalin-induced pain and that minocycline, an inhibitor of microglial activation, attenuate behavioral hypersensitivity in neuropathic pain models. We investigated whether minocycline could have any anti-nociceptive effect on inflammatory pain, after intraperitonial administration of minocycline, 1 h before formalin (5%, 50 microl) injection into the plantar surface of rat hindpaw. Minocycline (15, 30, and 45 mg/kg) significantly decreased formalin-induced nociceptive behavior during phase II, but not during phase I. The enhancement in the number of c-Fos-positive cells in the L4-5 spinal dorsal horn (DH) and the magnitude of paw edema induced by formalin injection during phase II were significantly reduced by minocycline. Minocycline inhibited synaptic currents of substantia gelatinosa (SG) neurons in the spinal DH, whereas membrane electrical properties of dorsal root ganglion neurons were not affected by minocycline. Analysis with OX-42 antibody revealed the inhibitory effect of minocycline on microglial activation 3 days after formalin injection. These results demonstrate the anti-nociceptive effect of minocycline on formalin-induced inflammatory pain. In addition to the well-known inhibitory action of minocycline on microglial activation, the anti-edematous action in peripheral tissue, as well as the inhibition of synaptic transmission in SG neurons, is likely to be associated with the anti-nociceptive effect of minocycline.     

Complex regional pain syndrome

Abstract Complex regional pain syndrome (CRPS) may develop after limb trauma and is characterized by pain, sensory-motor and autonomic symptoms. Most important for the understanding of the pathophysiology of CRPS are recent results of neurophysiological research. Major mechanism for CRPS symptoms, which might be present subsequently or in parallel during the course of CRPS, are trauma-related cytokine release, exaggerated neurogenic inflammation, sympathetically maintained pain and cortical reorganisation in response to chronic pain (neuroplasticity). The recognition of these mechanisms in individual CRPS patients is the prerequisite for a mechanism-oriented treatment.     

Neurological findings in complex regional pain syndromes--analysis of 145 cases

Early diagnosis is a prerequisite for a successful treatment of complex regional pain syndrome (CRPS). In order to describe neurological symptoms which characterize CRPS, we evaluated 145 patients prospectively. Two-thirds of these were women, the mean age at time of investigation was 50.4 years. CRPS followed limb trauma, surgery and nerve lesion. Employing the current IASP criteria 122 patients were classified as CRPS I and 23 as CRPS II. All patients were assessed clinically pain was quantified using the McGill pain questionnaire, skin temperature was measured by an infrared thermometer and a subgroup of 57 patients was retested in order to determine thermal thresholds (QST). Of our patients 42% reported stressful life events in a close relationship to the onset of CRPS and 41% had a history of chronic pain before CRPS. The latter group of patients gave a higher rating of CRPS pain (P<0.05). The major symptoms were pain at rest in 77% and hyperalgesia in 94%. Typical pain was deep in the limb having a tearing character. Patients getting physical therapy had significantly less pain than those without (P<0.04). Autonomic signs were frequent (98%) and often changed with the duration of CRPS. Skin temperature was warmer in acute and colder in chronic stages (P<0.001). Likewise edema had a higher incidence in acute stages (P<0.001). We found no correlation between pain and autonomic dysfunction. Motor dysfunction (present in 97%) included weakness, tremor, exaggerated tendon reflexes, dystonia or myoclonic jerks. QST revealed increased warm perception thresholds (P<0.02) and decreased cold pain thresholds (P<0.03) of the affected limb. The detailed knowledge of clinical features of CRPS could help physicians early to recognize the disease and thus to improve therapy outcome.     

Usefulness of thermography in the diagnosis and classification of complex regional pain syndrome

IntroductionWe propose a protocol for study of complex regional pain syndrome (CRPS) based on a battery of quantitative measures (skin thermography, electrochemical skin conductance and sensory thresholds) and apply such protocol to 5 representative cases of CRPS.Patients and methods5 CPRS cases (2 women/3 men) that met the Budapest criteria for the diagnosis of CRPS.ResultsAll patients showed spontaneous pain and allodynia. Two cases correspond to a stage I, in both the resting basal temperature was increased in the affected limb. Three cases reflect more advanced stages with a decrease in resting temperature and a delay in the recovery of the temperature when compared to contralateral limb.DiscussionThese non-invasive quantitative functional tests not only improve the diagnostic accuracy of CRPS but also, they help us to stratify and understand the pathological processes of the disease.     

Effects of ZD6169, a K ATP channel opener, on neurally-mediated plasma extravasation in the rat urinary bladder induced by chemical or electrical stimulation of nerves

The effects of oral administration of ZD6169, a potassium channel opener, on neurally mediated plasma extravasation in the urinary bladder and urethra were examined in urethane-anesthetized rats. Plasma extravasation was evaluated by measuring the tissue concentration of Evans blue, administered intravenously (50 mg/kg) 15 min prior to removal of tissues. Plasma extravasation was induced by three different stimuli: intravesical administration of either 0.25% acetic acid or 100 microM capsaicin or electrical stimulation of the pelvic nerve on one side (50 V, 10 s trains, 30 Hz intra-train frequency at 1 min intervals for 40 min). ZD6169 (5 mg/kg), administered orally 5 h prior to stimulation, significantly reduced the capsaicin-induced (50% decrease, p<0.05) or the electrical stimulation-induced (58% decrease, p<0.05) plasma extravasation in the bladder, but did not prevent the plasma extravasation in the bladder or urethra induced by intravesical infusion of 0.25% acetic acid. Administration of a K(ATP) channel blocker, glibenclamide (20 mg/kg, iv) 45 min prior to ZD6169 administration blocked the effects of ZD6169 on the electrical stimulation-induced plasma extravasation in the bladder and reduced the effects of ZD6169 on capsaicin-induced plasma extravasation. These findings indicate that ZD6169 (and/or a metabolite) can reduce neurogenic plasma extravasation in the bladder and are consistent with other studies indicating that ZD6169 can activate K(ATP) channels in C-fiber bladder afferents and suppress afferent activity.     

Antidromic vasodilatation in the rat hindpaw measured by laser Doppler flowmetry: pharmacological modulation

Antidromic vasodilatation in the hindpaw skin of rats was studied by laser Doppler flowmetry (LDF). Antidromic stimulation of the saphenous nerve (10 V, 1 ms, 2 Hz, 15 s) increased LDF readings more than two-fold. This increase was abolished by acute nerve section, local lidocain or local 1% capsaicin, augmented by guanethidine (20 mg/kg) and unaffected by atropine (1 mg/kg). While mepyramine plus cimetidine (10 mg/kg each) reduced basal LDF readings, they did not change the percent increase after stimulation. [D-Met2, Pro5] enkephalinamide (3 mg/kg) caused a naloxone-reversible inhibition of the stimulation-induced increase. Lofentanil (10 micrograms/kg i.v.) also caused an inhibition but this was associated with a marked fall in blood pressure. These results indicate that LDF is a suitable non-invasive method for the indirect measurement of antidromic vasodilatation in rat skin. While opiates appear to inhibit the release of the neurogenic vasoactive mediator(s), histamine is unlikely to be involved in the rapid vasodilator response following antidromic sensory nerve stimulation.     

Comparison of the Anti-inflammatory and Anti-nociceptive Effects of Cortistatin-14 and Somatostatin-14 in Distinct In Vitro and In Vivo Model Systems

We showed that somatostatin (SST) exerts anti-inflammatory and anti-nociceptive effects through somatostatin receptor subtypes 4 and 1 (sst₄/sst₁). Since cortistatin (CST) is a structurally similar peptide, we aimed at comparing the sst₁- and sst₄-binding and activating abilities, as well as the effects of SST-14 and CST-14 on inflammatory and nociceptive processes. CST-14 concentration-dependently displaced radiolabeled SST-14 binding, induced similar sst₁ and sst₄-activation with a less potency, and exerted significantly greater inhibitory effect on endotoxin-stimulated interleukin (IL)-1β production of murine peritoneal macrophages. Capsaicin-induced calcitonin gene-related peptide release from peripheral sensory nerve terminals of isolated rat tracheae was significantly decreased by 2 μM CST and 100 nM SST, but concentration-response correlation was not found. Mustard oil-evoked acute neurogenic plasma protein extravasation in the rat hindpaw skin, carrageenan-induced mouse paw edema, mechanical hyperalgesia, and IL-1β, tumor necrosis factor-α production, as well as mild heat injury-evoked thermal hyperalgesia were similarly attenuated by both peptides. In the latter case, i.pl. and i.p. injections exerted equal inhibitory actions. CST-14 and SST-14 similarly diminish both acute neurogenic and cellular inflammatory processes, as well as mechanical and heat hyperalgesia, in which their inhibitory effect on sensory nerve endings is likely to be involved. However, CST-14 exerts remarkably greater inhibition on cytokine production.     

Continuous but not intermittent olanzapine infusion induces vacuous chewing movements in rats.

BACKGROUND: Continuous, but not intermittent, infusion with a conventional antipsychotic (haloperidol, HAL) can induce the vacuous chewing movement (VCM) syndrome in rats. The objective of this study was to determine whether continuous, versus intermittent, olanzapine (OLZ) infusion differently affects the development of VCMs. METHODS: Experiment 1: Animals were treated with 7.5 mg/kg/day of OLZ or vehicle (VEH) via either minipump (MP) or daily subcutaneous (SC) injections for 8 weeks. Experiment 2: A separate group of rats were treated with 15 mg/kg/day of OLZ, or 1 mg/kg/day of HAL or VEH via MP for 8 weeks. Dopamine D2 receptor occupancy levels were measured, ex vivo, with [3H]-raclopride. RESULTS: Experiment 1: Rats receiving 7.5 mg/kg/day of OLZ via MP (51% D2 occupancy), but not those receiving the same dose via daily SC injections (94% peak D2 occupancy), showed significant VCM levels compared with control animals (p = .02). Experiment 2: Both OLZ (67% D2 occupancy) and HAL (79% D2 occupancy) led to similar increases in VCMs compared with VEH (p = .005). CONCLUSIONS: This study provides strong evidence that even an atypical antipsychotic like OLZ, which rarely gives rise to tardive dyskinesia in the clinic, can lead to the VCM syndrome in rats if the antipsychotic is administered in a method (via MP) that leads to continuous presence of the drug in the brain.     

Long-term effects of methylprednisolone following transection of adult rat spinal cord.

Clinically, high-dose treatment with the glucocorticosteroid, methylprednisolone (MP), within 8 h after spinal cord injury, has been shown to improve neurological recovery. The current standard of care is to administer MP as a bolus of 30 mg/kg followed by a 23-h infusion of 5.4 mg/kg/h to spinal cord injured patients. To better understand the role of MP in neuroprotection, we have studied how MP administration affects macrophage accumulation, tissue loss, and axonal dieback at 1, 2, 4 and 8 weeks after a complete transection of the eighth thoracic spinal cord in the adult rat. A 30 mg/kg dose of MP was administered intravenously at 5 min, and 2 and 4 h after injury. The number of ED1 (antibody against microglia/macrophages) -positive cells was quantified in a 500-micrometer-wide strip of tissue directly adjacent and parallel to the transection. At all time points, MP treatment led to a significant decrease in the number of ED1-positive cells in both rostral and caudal stumps. Over the 2-month post-transection period, the average MP-induced reduction in the number of ED1-positive cells was 82% in the rostral cord stump and 66% in the caudal stump. Using a computerized image analysis system, it was observed that MP treatment resulted in a significant reduction in tissue loss in both cord stumps at 2, 4 and 8 week post-injury. Over the 2-month post-lesion period, the average MP-induced reduction in tissue loss in the caudal cord stump was higher than that in the rostral stump; 48 versus 37%, respectively. Immunostaining for neurofilaments and growth-associated protein-43 (GAP-43) revealed the presence of numerous axons near and in the lesion site. Anterograde neuronal tracing with biotinylated dextran amine showed that, in MP-treated animals, dieback of vestibulospinal fibres, but not of corticospinal fibres, was significantly diminished at all time points studied. In addition, with MP administration, 1 and 2 weeks after injury, an increase in the number of vestibulospinal fibres was found at 1 and 2 mm from the transection, suggesting transient regenerative sprouting of these fibres. The results demonstrate that treatment with MP shortly after spinal cord transection in the adult rat led to a long-term reduction of ED1-positive cells and spinal tissue loss, reduced dieback of vestibulospinal fibres, and a transient sprouting of vestibulospinal fibres near the lesion at 1 and 2 weeks post-lesion. The possible relationships between the inflammatory changes, spinal tissue sparing, and axonal survival and sprouting are complex and need to be further explored.     

Local capsaicin application to the stellate ganglion and stellatectomy attenuate neurogenic inflammation in rat bronchi.

The present study investigated the contributions of vagal and nonvagal sensory nerve fibers on neurogenic inflammation in rat bronchial airways. A surgical procedure was developed via the rat mediastinum ventral intercostal space to prepare an intercostal opening without causing pneumothorax for performing stellate ganglionectomy alone, thoracic vagus nerve section alone, and stellatectomy plus thoracic vagotomy, and for injecting capsaicin (2 microl, 10 mg/ml) and 6-hydroxydopamine (2 microl, 50 mg/ml) into the ganglion. One week later in our procedure, we investigated if neurogenic inflammation induced by an intravenous injection of capsaicin (300 nmol/ml/kg) and innervation density of substance P-immunoreactive sensory axons could be decreased after chronic denervation in the rat lower airways. The major findings were that surgical removal of the right stellate ganglion and local capsaicin application resulted in a significant attenuation of neurogenic plasma extravasation in the right bronchial tree evoked by systemic capsaicin application. Reduction of neurogenic plasma extravasation was totally abolished by combined stellatectomy and thoracic vagotomy. The number of substance P-containing axons was also greatly decreased following these surgical and capsaicin treatments. It is concluded that sensory nerve fibers from both vagal source and nonvagal (spinal) source, which associated with the stellate ganglion, contributed significantly to neurogenic inflammation in the bronchial airways with a slightly higher contribution from the vagus nerve.     

alpha-eudesmol, a P/Q-type Ca(2+) channel blocker, inhibits neurogenic vasodilation and extravasation following electrical stimulation of trigeminal ganglion

In this study, we investigated the effect of alpha-eudesmol, which potently inhibits the presynaptic omega-agatoxin IVA-sensitive (P/Q-type) Ca(2+) channel, on neurogenic inflammation following electrical stimulation of rat trigeminal ganglion. Treatment with alpha-eudesmol (0.1-1 mg/kg. i.v.) dose-dependently attenuated neurogenic vasodilation in facial skin monitored by a laser Doppler flowmetry. In addition, alpha-eudesmol (1 mg/kg. i.v.) significantly decreased dural plasma extravasation in analysis using Evans blue as a plasma marker. On the other hand, alpha-eudesmol (1 mg/kg, i.v.) did not affect mean arterial blood pressure in rats. The calcitonin gene-related peptide (CGRP) and substance P (SP) released from activated sensory nerves have recently been suggested to be associated with the neurogenic inflammation. In this study, we also showed that alpha-eudesmol (0.45-45 microM) concentration-dependently inhibits the depolarization-evoked CGRP and SP release from sensory nerve terminals in spinal cord slices. These results indicate that the anti-neurogenic inflammation action of alpha-eudesmol, which does not affect the cardiovascular system, may be due to its presynaptic inhibition of the neuropeptide release from perivascular trigeminal terminals. We also suggest that the omega-agatoxin IVA-sensitive Ca(2+) channel blocker, alpha-eudesmol, may become useful for the treatment of the neurogenic inflammation in the trigemino-vascular system such as migraine.     

Spreading of complex regional pain syndrome: not a random process

Complex regional pain syndrome (CRPS) generally remains restricted to one limb but occasionally may spread to other limbs. Knowledge of the spreading pattern of CRPS may lead to hypotheses about underlying mechanisms but to date little is known about this process. The objective is to study patterns of spread of CRPS from a first to a second limb and the factors associated with this process. One hundred and eighty-five CRPS patients were retrospectively evaluated. Cox’s proportional hazards model was used to evaluate factors that influenced spread of CRPS symptoms. Eighty-nine patients exhibited CRPS in multiple limbs. In 72 patients spread from a first to a second limb occurred showing a contralateral pattern in 49%, ipsilateral pattern in 30% and diagonal pattern in 14%. A trauma preceded the onset in the second limb in 37, 44 and 91%, respectively. The hazard of spread of CRPS increased with the number of limbs affected. Compared to patients with CRPS in one limb, patients with CRPS in multiple limbs were on average 7 years younger and more often had movement disorders. In patients with CRPS in multiple limbs, spontaneous spread of symptoms generally follows a contralateral or ipsilateral pattern whereas diagonal spread is rare and generally preceded by a new trauma. Spread is associated with a younger age at onset and a more severely affected phenotype. We argue that processes in the spinal cord as well as supraspinal changes are responsible for spontaneous spread in CRPS.     

Alpha-adrenergic systems mediate chronic central AII hypertension in rats fed high sodium chloride diet from weaning.

Hypertension is elicited by chronic, low dose intracerebroventricular (ICV) angiotensin II (AII) infusion in rats raised from weaning on relatively high sodium chloride diet (250 mEq kg(-1) food). This experimental model of hypertension is dependent upon renal innervation and associated with neurogenic sodium retention. The present study determined whether this neurogenic ICV AII hypertension is mediated by central alpha-adrenoceptors. Rats were weaned at 21 days of age and fed a 1.5% (250 mg kg(-1) food) sodium chloride diet for 10-12 weeks. At adulthood, animals were instrumented with central nervous system (CNS) lateral ventricular cannulas, femoral artery and vein catheters and housed in metabolic pens for chronic study. Low dose ICV AII infusion (20 ng min(-1)) increased mean arterial pressure (MAP) from 121 +/- 4 to 140 +/- 6 mm Hg on the day of ICV infusion. This increase in arterial pressure was associated with 3 consecutive days of decreased urinary sodium excretion. Subsequent ICV alpha-adrenoceptor blockade with phentolamine (AII + phentolamine) abolished the pressor and antinatriuretic responses to low dose chronic ICV AII infusion. Resumption of ICV AII infusion alone increased in MAP toward pre-alpha-adrenergic blockade values (133 +/- 5 mm Hg) on day 8. Following cessation of ICV AII infusion, arterial pressure and sodium excretion returned to values not significantly different from control. This model of hypertension was not dependent on circulating plasma renin activity (PRA), since PRA decreased during ICV AII infusion. These data confirm that low dose ICV AII causes hypertension and sodium retention in rats raised from weaning on moderately elevated sodium intake. We conclude that AII mediated neurogenic hypertension and antinatriuresis is elicited by stimulation of AT1 receptors on neurons which interact with noradrenergic cell bodies in cardiovascular and autonomic centers that may modulate renal sympathetic outflow via alpha-adrenoceptors.     

Autonomic failure after stroke – is it indicative for pathophysiology of complex regional pain syndrome?

In order to find pieces of evidence for a central origin of autonomic failure in complex regional pain syndrome I (CRPS I), the pattern of autonomic symptoms in CRPS I patients was compared to patients a few days after stroke. Autonomic failure in the latter group is assumed to represent definite CNS origin. Seventeen stroke patients, 21 patients in the acute and late stage of CRPS I and a control group of 23 healthy subjects were investigated. Detailed neurological examination was performed, sweating was induced centrally (thermoregulatory sweating, TST) and peripherally by carbachol iontophoresis (QSART) and quantified by evaporation hygrometry. Skin temperature was assessed by infrared thermography. The incidence of motor-sensory dysfunction (without pain) and the incidence of edema was strikingly similar in stroke and CRPS patients. Furthermore, stroke patients had increased TST but not QSART responses on the contralesional limb (P < 0.05) and skin temperature was decreased (P < 0.001). The same pattern of autonomic failure was found in late CRPS (TST: P < 0.02, skin temperature: P < 0.01) whereas in acute CRPS additional, presumably peripheral mechanisms, contribute to sympathetic symptoms. In conclusion, our investigation suggests that many clinical symptoms and the main features of sympathetic dysfunction in CRPS could be explained by a CNS pathophysiology.     

Involvement of Substance P in Ultraviolet Irradiation-induced Inflammation in Rat Skin

The possible involvement of substance P released from primary afferents in rat skin was investigated in cutaneous inflammation following ultraviolet (UV) irradiation. Recordings from c-fibres innervating the UV-exposed hindpaw skin showed long-lasting low-frequency (0.8–1.25 Hz) spontaneous activity. Spontaneously active c-fibres increased to constitute 35.3% of the total population 72 h after UV exposure. Immunohisto-chemical analysis of substance P-containing nerve fibres in hindpaw skin revealed a significant increase in substance P immunoreactivity 24 h after UV irradiation. Average length of substance P-immunolabelled nerve fibres was about two times higher in UV-exposed compared to control skin. UV-induced oedema was investigated in rat ears using an ear-swelling test. Intradermal injection of either peptide (Spantide) or non-peptide (CP-96,345) substance P antagonists and epicutaneous application of CP-96,345 reduced UV-induced oedema significantly in the late phase of sunburn (>12 h after UV exposure). The UV-induced increase in skin blood flow was investigated in hindpaw skin up to 72 h by the laser Doppler technique. Epicutaneous application of CP-96,345 reduced erythema significantly between 12 and 72 h after UV exposure. Thus, our findings suggest the involvement of neurogenic substance P as a proinflammatory mediator in the late phase of UV-induced cutaneous inflammation in rats.