endothelin-1 and Reflex-Sympathetic-Dystrophy

We have recently demonstrated a role of the vascular endothelium in peripheral pain mechanism by disrupting endothelial cell function using intravascular administration of octoxynol-9, a non-selective membrane active agent. As an independent test of the role of endothelial cells in pain mechanisms, we evaluated the effect of homocysteine, an agent that damages endothelial cell function. Mechanical stimulus-induced enhancement of endothelin-1 hyperalgesia in the gastrocnemius muscle of the rat was first prevented then enhanced by intravenous administration of homocysteine, but was only inhibited by its precursor, methionine. Both homocysteine and methionine significantly attenuated mechanical hyperalgesia in two models of ergonomic muscle pain, induced by exposure to vibration, and by eccentric exercise, and cutaneous mechanical hyperalgesia in an ischemia-reperfusion injury model of Complex Regional Pain Syndrome type I, all previously shown responsive to octoxynol-9. This study provides independent support for a role of the endothelial cell in pain syndromes thought to have a vascular basis, and suggests that substances that are endothelial cell toxins can enhance vascular pain.

Topics: Analgesics, Non-Narcotic; Animals; Cardiovascular Agents; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Homocysteine; Hyperalgesia; Hypoxia-Ischemia, Brain; Male; Methionine; Movement; Muscle, Skeletal; Myalgia; Rats, Sprague-Dawley; Reflex Sympathetic Dystrophy; Touch; Vibration

Complex regional pain syndrome (CRPS) is a very complicated chronic pain disorder that has been classified into two types (I and II). Endothelin (ET) receptors are involved in pain conditions at the spinal level. We investigated the role of spinal ET receptors in CRPS. Chronic post-ischemia pain (CPIP) was induced in male Sprague-Dawley rats as a model for CRPS-I by placing a tourniquet (O-ring) at the ankle joint for 3h, and removing it to allow reperfusion. Ligation of L5 and L6 spinal nerves to induce neuropathic pain was performed as a model for CRPS-II. After O-ring application and spinal nerve ligation, the paw withdrawal threshold was significantly decreased at injured sites. Intrathecal administration of the selective ET-B receptor antagonist BQ 788 dose-dependently increased the withdrawal threshold in both CRPS-I and CRPS-II. In contrast, ET-A receptor antagonist BQ 123 did not affect the withdrawal threshold in either CRPS type. The ET-1 levels of plasma and spinal cord increased in both CRPS types. Intrathecal BQ 788 decreased the spinal ET-1 level. These results suggest that ET-1 is involved in the development of mechanical allodynia in CRPS. Furthermore, the ET-B receptor appears to be involved in spinal cord-related CRPS.

Topics: Animals; Causalgia; Endothelin B Receptor Antagonists; Endothelin-1; Hyperalgesia; Male; Oligopeptides; Pain Threshold; Peptides, Cyclic; Physical Stimulation; Piperidines; Rats, Sprague-Dawley; Reflex; Reflex Sympathetic Dystrophy; Spinal Cord; Touch

Chronic post-ischemic pain (CPIP) is an animal model of CRPS-I developed using a 3-h ischemia-reperfusion injury of the rodent hind paw. The contribution of local endothelin to nociception has been evaluated in CPIP mice by measuring sustained nociceptive behaviors (SNBs) following intraplantar injection of endothelin-1 or -2 (ET-1, ET-2). The effects of local BQ-123 (ETA-R antagonist), BQ-788 (ETB-R antagonist), IRL-1620 (ETB-R agonist) and naloxone (opioid antagonist) were assessed on ET-induced SNBs and/or mechanical and cold allodynia in CPIP mice. ETA-R and ETB-R expression was assessed using immunohistochemistry and Western blot analysis. Compared to shams, CPIP mice exhibited hypersensitivity to local ET-1 and ET-2. BQ-123 reduced ET-1- and ET-2-induced SNBs in both sham and CPIP animals, but not mechanical or cold allodynia. BQ-788 enhanced ET-1- and ET-2-induced SNBs in both sham and CPIP mice, and cold allodynia in CPIP mice. IRL-1620 displayed a non-opioid anti-nociceptive effect on ET-1- and ET-2-induced SNBs and mechanical allodynia in CPIP mice. The distribution of ETA-R and ETB-R was similar in plantar skin of sham and CPIP mice, but both receptors were over-expressed in plantar muscles of CPIP mice. This study shows that ETA-R and ETB-R have differing roles in nociception for sham and CPIP mice. CPIP mice exhibit more local endothelin-induced SNBs, develop a novel local ETB-R agonist-induced (non-opioid) analgesia, and exhibit over-expression of both receptors in plantar muscles, but not skin. The effectiveness of local ETB-R agonists as anti-allodynic treatments in CPIP mice holds promise for novel therapies in CRPS-I patients.

Topics: Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelins; Hyperalgesia; Keratinocytes; Male; Mice; Muscle, Skeletal; Naloxone; Narcotic Antagonists; Oligopeptides; Pain Measurement; Pain Threshold; Peptide Fragments; Peptides, Cyclic; Peripheral Nervous System; Physical Stimulation; Piperidines; Receptors, Endothelin; Reflex Sympathetic Dystrophy; Skin

In complex regional pain syndrome type 1 (CRPS1) vascular changes occur from the initial, inflammatory event onto the trophic signs during chronicity of the disease, resulting in blood flow disturbances and marked temperature changes. Pharmacotherapeutic treatment is generally inadequate.. To determine whether local application of the nitric oxide donor isosorbide dinitrate (ISDN) could cause vasodilation and thereby improve tissue blood distribution in the affected extremity.. In a pilot study, 5 female patients with CRPS1 in one hand were treated with ISDN ointment 4 times daily during 10 weeks. As a primary objective videothermography was used to monitor changes in blood distribution in both the involved and contralateral extremities.. Patients treated with ISDN showed an increase of 4 degrees C to 6 degrees C in mean skin temperature of the cold CRPS1 hands, reaching values similar to that of the contralateral extremities within 2 to 4 weeks time, suggesting normalization of blood distribution. This was confirmed by an improvement in skin color. In 3 patients the Visual Analog Scale pain declined, whereas in the other 2 patients the Visual Analog Scale pain was unchanged over time.. In this pilot study, topical application of ISDN seems to be beneficial to improve symptoms for patients with cold type CRPS1, but further study is needed.

Topics: Administration, Topical; Endothelin-1; Female; Functional Laterality; Humans; Isosorbide Dinitrate; Microcirculation; Middle Aged; Muscle Contraction; Muscle, Skeletal; Nitric Oxide; Ointments; Pain Measurement; Pilot Projects; Reflex Sympathetic Dystrophy; Skin Temperature; Thermography; Vasodilator Agents

In complex regional pain syndrome type 1 (CRPS1) pro-inflammatory mediators and vascular changes play an important role in the sustained development and outcome of the disease. The aim of this study was to determine the involvement of vasoactive substances endothelin-1 (ET-1) and nitric oxide (NO) during early chronic CRPS1.. Included were 29 patients with CRPS 1 who were diagnosed during the acute stage of their disease and observed during follow-up visits. Disease activity and impairment were determined and artificial suction blisters were made on the CRPS1 and the contralateral extremities for measurements of IL-6, TNF-alpha, ET-1 and nitrate/nitrite (NOx).. The levels of IL-6, TNF-alpha and ET-1 in blister fluid in the CRPS1 extremity versus the contralateral extremity were significantly increased and correlated with each other, whereas NOx levels were decreased.. The NOx/ET-1 ratio appears to be disturbed in the intermediate stage of CRPS, resulting in vasoconstriction and consequently in a diminished tissue blood distribution.

Topics: Adult; Biomarkers; Blister; Dermatitis; Down-Regulation; Endothelin-1; Female; Humans; Inflammation Mediators; Interleukin-6; Male; Microcirculation; Middle Aged; Nitric Oxide; Predictive Value of Tests; Reflex Sympathetic Dystrophy; Regional Blood Flow; Skin; Tumor Necrosis Factor-alpha; Up-Regulation