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.

Perspective: 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.

Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1

Assessment of the effects of single topical agents clonidine, apraclonidine, linsidomine, SNAP, pentoxifylline and lisofylline (A–F) on paw-withdrawal thresholds (PWTs) to von Frey stimulation of the ipsilateral (injured) hind paw in day 2–14 CPIP rats. Singly, each agent produces dose-related anti-allodynic effects, with higher concentrations producing significant elevations of PWTs and the lowest concentrations failing to produce significant anti-allodynic effects. *P < 0.05 between pre- and post-drug mean PWTs.

Fig 2

Assessment of the effects of topical combinations of pentoxifylline or lisofylline given with either vehicle or ineffective concentrations of clonidine (A,B), linsidomine (C,D) and SNAP (E,F) on paw-withdrawal thresholds (PWTs; A,C,E) and anti-allodynic (ΔPWT) pentoxifylline or lisofylline dose-response curves alone or in combination with clonidine, linsidomine or SNAP (B,D,F) in the ipsilateral (injured) hind paw of day 2–14 CPIP rats. The combinations significantly increased PWTs at concentrations much lower than in Fig. 1, and shifted the anti-allodynic dose-response curve for lisofylline between 2 and 10 fold to the left. *P < 0.05 between pre- and post-drug mean PWTs.

Fig. 3

Comparison of the effects of topical vehicle application, or ipsilateral versus contralateral application of the most effective concentrations of the topical combinations used in Figs. 2 (clonidine + pentoxifylline (A), linsidomine + lisofylline (B) and SNAP + lisofylline (C)) on paw-withdrawal thresholds (PWTs) in the ipsilateral (injured) hind paw of day 2–14 CPIP rats. In all trials, topical application of vehicle failed to significantly alter PWTs. Furthermore, although each combination significantly increased PWTs when applied to ipsilateral hind paw, they were all ineffective when applied to the contralateral hind paw. *P < 0.05 between pre- and post-drug mean PWTs; †P < 0.05 from post-drug vehicle; ‡P < 0.05 from post-drug contralateral PWT.

Fig. 4

Comparison of the effects of topical vehicle administration, or ipsilateral versus contralateral administration of the effective concentrations of four topical combinations (clonidine + pentoxifylline (A), apraclonidine + lisofylline (B) linsidomine + pentoxifylline (C) and SNAP + lisofylline (C)), on paw-withdrawal thresholds (PWTs) in the ipsilateral (injured) hind paw of day 7–14 CCI rats. In all trials, topical application of vehicle failed to significantly alter PWTs. Furthermore, although each combination significantly increased PWTs when applied to ipsilateral hind paw, they were all ineffective when applied to the contralateral hind paw. *P < 0.05 between pre- and post-drug mean PWTs. †P < 0.05 from post-drug vehicle. ‡P < 0.05 from post-drug contralateral PWT.

Fig. 5

Time course of the anti-allodynic effects of low concentration topical combinations of apraclonidine + pentoxifylline (A,B), apraclonidine + lisofylline (C,D) and linsidomine + lisofylline (E,F) on paw-withdrawal thresholds (PWTs) both ipsilateral and contralateral to the topical treatments in rats with streptozotocin (STZ)-induced diabetic neuropathy (A,C,E) or in age-matched vehicle-injected controls (B,D,F). Each topical combination significantly increased PWTs of the ipsilateral (treated), but not the contralateral (untreated) hind paws of rats with diabetic neuropathy. Conversely, the topical combinations had no effects on PWTs in the ipsilateral or contralateral hind paws in age-matched (STZ vehicle-injected) control rats. *P < 0.05 between pre- and post-drug mean PWTs within a group. †P < 0.05 between ipsi- and contralateral PWTs, and ¶P < 0.05 between diabetic and control PWTs at each time point.

Fig. 6

Anti-allodynic effects over an acute time course (A,B) and chronic daily dosing (C,D) of topical combinations of apraclondine + lisofylline (A,C) or linsidomine + pentoxifylline (B,D) in rats with CIPN. Each combination produced acute anti-allodynic effects lasting 6 h after the first topical application (*P