title: Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain.
abstract: Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α(2)-adrenergic (α(2)A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α(2)A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α(2)A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain.
  
  
  CONCLUSIONS
  This article presents the synergistic antiallodynic effects of combinations of α(2)A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas.
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
authors.forename: J Vaigunda
authors.initials: JV
authors.lastname: Ragavendran
authors.forename: André
authors.initials: A
authors.lastname: Laferrière
authors.forename: Wen Hua
authors.initials: WH
authors.lastname: Xiao
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bennett
authors.forename: Satyanarayana S V
authors.initials: SS
authors.lastname: Padi
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.forename: Terence J
authors.initials: TJ
authors.lastname: Coderre
mesh_terms: D000287:Administration, Topical; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D002626:Chemistry, Pharmaceutical; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003929:Diabetic Neuropathies / Q000188:drug therapy; D004338:Drug Combinations; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000627:therapeutic use*; D009824:Ointments; D010101:Oxygen Consumption; D010147:Pain Measurement / Q000187:drug effects; D010712:Phosphatidic Acids / Q000037:antagonists & inhibitors*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012019:Reflex Sympathetic Dystrophy / Q000188:drug therapy* / Q000503:physiopathology*; D012039:Regional Blood Flow / Q000187:drug effects; D020426:Sciatic Neuropathy / Q000188:drug therapy
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D004338:Drug Combinations; D020030:Nitric Oxide Donors; D009824:Ointments; D010712:Phosphatidic Acids; D010726:Phosphodiesterase Inhibitors