title: Topical combinations to treat microvascular dysfunction of chronic postischemia pain.
abstract: BACKGROUND
  Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle, and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain.
  
  
  METHODS
  Mechanical allodynia was induced in the hindpaws of rats with chronic postischemia pain (CPIP). Allodynia was assessed before and after topical application of vehicle, single drugs or combinations of an α2A receptor agonist (apraclonidine) or an NO donor (linsidomine), with PA or PDE inhibitors (lisofylline, pentoxifylline). A topical combination of apraclonidine + lisofylline was also evaluated for its effects on a measure of microvascular function (postocclusive reactive hyperemia) and tissue oxidative capacity (formazan production by tetrazolium reduction) in CPIP rats.
  
  
  RESULTS
  Each of the single topical drugs produced significant dose-dependent antiallodynic effects compared with vehicle in CPIP rats (N = 30), and the antiallodynic dose-response curves of either PA or PDE inhibitors were shifted 5- to 10-fold to the left when combined with nonanalgesic doses of α2A receptor agonists or NO donors (N = 28). The potent antiallodynic effects of ipsilateral treatment with combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors were not reproduced by the same treatment of the contralateral hindpaw (N = 28). Topical combinations produced antiallodynic effects lasting up to 6 hours (N = 15) and were significantly enhanced by low-dose systemic pregabalin in early, but not late, CPIP rats (N = 18). An antiallodynic topical combination of apraclonidine + lisofylline was also found to effectively relieve depressed postocclusive reactive hyperemia in CPIP rats (N = 61) and to increase formazan production in postischemic tissues (skin and muscle) (N = 56).
  
  
  CONCLUSIONS
  The present results support the hypothesis that allodynia in an animal model of CRPS is effectively relieved by topical combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors. This suggests that topical treatments aimed at improving microvascular function by increasing both arterial and capillary blood flow produce effective analgesia for CRPS.
authors.affiliation: From the *Alan Edwards Centre for Research on Pain, Department of Anesthesia, †Department of Psychology, ‡Alan Edwards Centre for Research on Pain, Department of Anesthesia, Neurology and Neurosurgery, and Psychology, and §Anesthesia Research Unit, McGill University Health Centre Research Institute, Montreal, QC, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Laferrière
authors.forename: Rachid
authors.initials: R
authors.lastname: Abaji
authors.forename: Cheng-Yu Mark
authors.initials: CY
authors.lastname: Tsai
authors.forename: J Vaigunda
authors.initials: JV
authors.lastname: Ragavendran
authors.forename: Terence J
authors.initials: TJ
authors.lastname: Coderre
mesh_terms: D000287:Administration, Topical; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002196:Capillaries / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D059350:Chronic Pain / Q000188:drug therapy* / Q000503:physiopathology*; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006930:Hyperalgesia / Q000188:drug therapy; D006940:Hyperemia / Q000503:physiopathology; D007511:Ischemia / Q000150:complications*; D017078:Laser-Doppler Flowmetry; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000627:therapeutic use; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology; D009824:Ointments; D010147:Pain Measurement / Q000187:drug effects; D010712:Phosphatidic Acids / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D012039:Regional Blood Flow / Q000187:drug effects
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D004338:Drug Combinations; D020030:Nitric Oxide Donors; D009824:Ointments; D010712:Phosphatidic Acids; D010726:Phosphodiesterase Inhibitors; C002385:linsidomine; C016986:apraclonidine; D008981:Molsidomine; D003000:Clonidine