Norepinephrine-induced nociception and vasoconstrictor hypersensitivity in rats with chronic post-ischemia pain

Self Cite

Chronic pain that responds to antisympathetic treatments and α-adrenergic antagonists is clinically referred to as sympathetically maintained pain. Animal models of neuropathic pain have shown mixed results in terms of antinociceptive effectiveness of antisympathetic agents. The effectiveness of these agents have not been yet investigated in animal models of complex regional pain syndrome-type 1 (CRPS-I). In this study, we examined the effectiveness of antisympathetic agents and sympathetic vasoconstrictor antagonists, as well as agents that are vasodilators, in relieving mechanical allodynia in a recently developed animal model of CRPS-I (chronic postischemia pain or CPIP) produced by three hours of hind paw ischemia-reperfusion injury. Systemic guanethidine, phentolamine, clonidine, and prazosin are effective in reducing mechanical allodynia particularly at 2 days after reperfusion, and less so at 7 days after reperfusion. A nitric oxide donor vasodilator, SIN-1, also reduces mechanical allodynia more effectively at 2 days after reperfusion, but not at 7 days after reperfusion. These results suggest that the pain of CPIP, and possibly also CRPS-I, is relieved by reducing sympathetically mediated vasoconstriction, or enhancing vasodilatation. KeywordsComplex regional pain syndrome; ischemia-reperfusion injury; neuropathic pain; allodynia; sympathetic block; adrenergic receptors Complex regional pain syndrome-type I (CRPS-I) is a disorder that occurs after fracture, soft tissue or crush injury. 16 Symptoms of CRPS-I include spontaneous burning (cutaneous) and aching (deep) pain, hyperalgesia, allodynia, and disorders of vasomotor and sudomotor regulation. 27,57 CRPS-II is similar but also exhibits a clinically verified nerve injury. CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptAlthough controversial, sympathetic blocks are often reported to relieve CRPS pain. 10,29,68 CRPS pain is also relieved with α-adrenergic antagonists such as phentolamine or phenoxybenzamine, 48,52 agents that have been used as diagnostic tools for identifying socalled sympathetically maintained pain (SMP We recently introduced chronic postischemia pain (CPIP) as an animal model of CRPS-I produced after hind paw ischemia-reperfusion (I-R) injury.14 This animal model shows signs of I-R injury such as no-reflow and vascular abnormalities, as well as nociceptive and vascular hypersensitivity to norepinephrine. 38,78 The pain-relieving effects of antisympathetic agents have not previously been tested in animal models of CRPS-I. 21,22,71 In this report, we examine whether antisympathetic drugs, and agents that are vasodilators, are effective in reducing painful symptoms in this model. Thus, we test the effectiveness of sympathetic block with guanethidine, or systemic treatments with the α1-and α2-adrenergic antagonists prazosin and yohimbine, the α2-adrenergic agonist clonidine, and a nitric oxide donor, in relieving mechanical allodynia in CPIP rats at 2 and 7 days after reperfusion. Materials and Methods Animal...

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Sympathetic Vasoconstrictor Antagonism and Vasodilatation Relieve Mechanical Allodynia in Rats With Chronic Postischemia Pain

Xanthos

Coderre

2008

Self Cite

“…46 Importantly, after hind paw IR injury, rats with vasoconstrictive hypersensitivity to norepinephrine (vasospasms) are more likely to develop allodynia, as well as painful responses to intraplantar norepinephrine. 98 Similar to CRPS patients, 17 sympathetic blockade using guanethidine is more effective at relieving allodynia in rats when performed early after hind paw IR injury. 99 As well as vasospasms, rats with hind paw IR injuries develop no-reflow over a time course that parallels allodynia, and exhibit muscle ischemia and increased muscle lactate (as do CRPS patients 29 ) that is directly correlated with the allodynia.…”

Section: Role Of Microvascular Dysfunctionmentioning

confidence: 99%

Complex Regional Pain Syndrome: What's in a Name?

Coderre

2011

Self Cite

Within a two year period in the 1940's, two Boston physicians published dramatically opposing views on the underlying nature of a syndrome now known as complex regional pain syndrome (CRPS). Evans suggested, in several papers in [1946][1947], that sympathetic reflexes maintain pain and dystrophy in affected limbs. Foisie, in 1947, suggested arterial vasospasms were key in the etiology of this pain syndrome. Evans' hypothesis established the nomenclature for this syndrome for 60 years, and his term "reflex sympathetic dystrophy" guided clinical treatment and research activities over the same period. Foisie's proposed nomenclature was unrecognized, and had virtually no impact on the field. Recent evidence suggests that Evans' contribution to the field may have in fact lead clinicians and researchers astray all those years. This focus article on CRPS compares recent observations with these 2 earlier theories and asks the question --what if we had adopted Foisie's nomenclature from the beginning?

“…Over the past several years, we have generated evidence that pain in an animal model of complex regional pain syndrome type I (CRPS-I) depends on local microvascular dysfunction 14,56,93 . Evidence suggests that in rats with chronic post-ischemia pain (CPIP), and patients with CRPS, ischemic tissue injury leads to the generation of oxygen free radicals and pro-inflammatory cytokines which cause microvascular injury, including arterial vasospasm and capillary slow-flow/no-reflow in the blood vessels of muscle and nerve 56,93 .…”

Section: Introductionmentioning

confidence: 99%

Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain

Ragavendran

Laferrière

Xiao

et al. 2013

Self Cite

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 2A ) 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 anti-allodynic effects in rats with chronic post- CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript ischemia pain, and the anti-allodynic dose-response curves of PDE and PA inhibitors were shifted 2.5-10 fold leftward when combined with non-analgesic doses of α 2A receptor agonists or NO donors. Topical combinations also produced significant anti-allodynic 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 h 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 2A 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.Perspective-This article presents the synergistic anti-allodynic effects of combinations of α 2A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas.