Synergistic Interaction of a Gabapentin‐ Mangiferin Combination in Formalin‐Induced Secondary Mechanical Allodynia and Hyperalgesia in Rats Is Mediated by Activation of NO‐Cyclic GMP‐ATP‐Sensitive K⁺ Channel Pathway

Abstract

Preclinical Research Gabapentin is an anticonvulsant used to treat neuropathic pain. Mangiferin is an antioxidant that has antinociceptive and antiallodynic effects in inflammatory and neuropathic pain models. The purpose of this study was to determine the interaction between mangiferin and gabapentin in the development and maintenance of formalin-induced secondary allodynia and hyperalgesia in rats. Gabapentin, mangiferin, or their fixed-dose ratio combination were administrated peripherally. Isobolographic analyses was used to define the nature of the interaction of antiallodynic and/or antihyperalgesic effects of the two compounds. Theoretical ED values for the combination were 74.31 µg/paw and 95.20 µg/paw for pre- and post-treatment, respectively. These values were higher than the experimental ED values, 29.45 µg/paw and 37.73 µg/paw respectively, indicating a synergistic interaction in formalin-induced secondary allodynia and hyperalgesia. The antiallodynic and antihyperalgesic effect induced by the gabapentin/mangiferin combination was blocked by administration of L-NAME, the soluble guanylyl cyclase inhibitor, ODQ and glibenclamide. These data suggest that the gabapentin- mangiferin combination produces a synergistic interaction at the peripheral level. Moreover, the antiallodynic and hyperalgesic effect induced by the combination is mediated via the activation of an NO-cyclic GMP-ATP-sensitive K channel pathway. Drug Dev Res 78 : 390-402, 2017. © 2017 Wiley Periodicals, Inc.

Long-term imaging of dorsal root ganglia in awake behaving mice

“…The above results reveal persistent hyperactivity of sensory ganglion neurons over months after formalin injection, which may contribute to the development of chronic pain. Previous studies have shown that formalin-induced pain may persist for days after the initial injection 42,43 . Because formalin-induced spontaneous licking or flinching behavior was no longer present after the day of injection, we employed a two-compartment conditional place preference (CPP) test 44 to assess the presence or absence of ongoing pain 45 .…”