Anti-allodynic Effect of Mangiferin in Rats With Chronic Post-ischemia Pain: A Model of Complex Regional Pain Syndrome Type I

Abstract

The present study reproduces chronic post-ischemia pain (CPIP), a model of complex regional pain syndrome type I (CRPS-I), in rats to examine the possible transient and long-term anti-allodynic effect of mangiferin (MG); as well as its potential beneficial interactions with some standard analgesic drugs and sympathetic-mediated vasoconstriction and vasodilator agents during the earlier stage of the pathology. A single dose of MG (50 and 100 mg/kg, p.o.) decreased mechanical allodynia 72 h post-ischemia-reperfusion (I/R). MG 100 mg/kg, i.p. (pre- vs. post-drug) increased von Frey thresholds in a yohimbine and naloxone-sensitive manner. Sub-effective doses of morphine, amitriptyline, prazosin, clonidine and a NO donor, SIN-1, in the presence of MG were found to be significantly anti-allodynic. A long-term anti-allodynic effect at 7 and 13 days post-I/R after repeated oral doses of MG (50 and 100 mg/kg) was also observed. Further, MG decreased spinal and muscle interleukin-1β concentration and restored muscle redox status. These results indicate that MG has a transient and long-term anti-allodynic effect in CPIP rats that appears to be at least partially attributable to the opioid and α2 adrenergic receptors. Additionally, its anti-inflammatory and antioxidant mechanisms could also be implicated in this effect. The association of MG with sub-effective doses of these drugs enhances the anti-allodynic effect; however, an isobolographic analysis should be performed to define a functional interaction between them. These findings suggest the possible clinical use of MG in the treatment of CRPS-I in both early sympathetically maintained pain and long-term sympathetically independent pain.

Mangiferin: Possible uses in the prevention and treatment of mixed osteoarthritic pain

“…MG also decreased mechanical allodynia and spinal IL‐1β concentration in CPIP rats (Garrido‐Suárez et al, ). In agreement with this notion, it was of particular interest that M. indica L. aqueous stem bark extract (MSBE) formulations containing the MG available in Cuba decreased the area of dynamic allodynia in clinical studies, an outcome frequently utilized as an indicator of central sensitization maintained by peripheral inputs (Garrido‐Suárez, Garrido, Delgado, Bosch, & Rabí, ; Garrido‐Suárez, Rabí, Bosch, Garrido, & Delgado‐Hernández, ).…”

“…Recently, it was reported that MG restored the redox balance and decreased IL‐1β protein concentration in the ipsilateral paw muscles of chronic postischemia pain (CPIP) rats, in terms of attenuation of lipid peroxidation, protein damage, and NO oxidation products. In addition, MG restores GSH and superoxide dismutase to near physiological concentrations (Garrido‐Suárez et al, ). This model mimics the CRPS‐I symptomatology made by persistent deep tissue (muscle, bone, and nerve) microvascular pathology that leads to a combination of inflammatory and neuropathic pain processes (Coderre & Bennett, ).…”

“…On the other hand, PN may be involved in the mechanical allodynia and NMDA receptor‐mediated central sensitization in the CPIP model (Kwak et al, ; Kwak, Lim, & Baek, ). In addition, subeffective doses of morphine in the presence of MG were found to be significantly anti‐allodynic (Garrido‐Suárez et al, ). A synergistic effect of the combination morphine and NAC, as well as potent analgesia by a bifunctional compound μ opioid agonist/antioxidant, have been demonstrated in CPIP rats (Schiller et al, ).…”

“…A synergistic effect of the combination morphine and NAC, as well as potent analgesia by a bifunctional compound μ opioid agonist/antioxidant, have been demonstrated in CPIP rats (Schiller et al, ). In both, persistent pain and CPIP models, the effects of MG were in a yohimbine and naloxone‐sensitive manner, suggesting the implication of these receptors (Garrido‐Suárez et al, ; Garrido‐Suárez et al, ). This ability in addition to its anti‐inflammatory and antioxidant mechanisms could be an advantage in mixed OA pain.…”

“…This ability in addition to its anti‐inflammatory and antioxidant mechanisms could be an advantage in mixed OA pain. Preliminary preclinical evidence in CPIP rats and some clinical results in musculoskeletal pain using ECAM formulations suggests a potential favorable and safe interaction with conventional drugs, such as opioids, tricyclic antidepressants, NSAIDs, clonidine, and steroids, possibly by additive/or supra‐additive mechanisms (Garrido‐Suárez et al, ; Garrido‐Suárez et al, ; López‐Mantecón, Garrido, Delgado‐Hernández, & Garrido‐Suárez, ). Osteoarthritis becomes more common with age, and older adults are more vulnerable to adverse events; synergistic interactions of drug combinations might provide superior analgesia and fewer side effects than monotherapy by multiple mechanisms (Gilron, Jensen, & Dickenson, ).…”