Spinal
neuroinflammation plays a critical role in the genesis of
neuropathic pain. Accumulating data suggest that
abscisic acid (ABA), a
phytohormone, regulates inflammatory processes in mammals. In this study, we found that reduction of the LANCL2 receptor
protein but not the agonist ABA in the spinal cord is associated with the genesis of
neuropathic pain. Systemic or intrathecal administration of ABA ameliorates the development and pre-existence of
mechanical allodynia and heat
hyperalgesia in animals with partial sciatic nerve
ligation (pSNL). LANCL2 is expressed only in microglia in the spinal dorsal horn. Pre-emptive treatment with ABA attenuates activation of microglia and astrocytes, ERK activity, and TNFα
protein abundance in the dorsal horn in rats with pSNL. These are accompanied by restoration of spinal LANCL2
protein abundance. Spinal knockdown of LANCL2 gene with
siRNA recapitulates the behavioral and spinal molecular changes induced by pSNL. Activation of spinal
toll-like receptor 4 (TLR4) with
lipopolysaccharide leads to activation of microglia, and over production of TNFα, which are concurrently accompanied by suppression of
protein levels of LANCL2 and
peroxisome proliferator activated-receptor γ. These changes are ameliorated when ABA is added with LPS. The anti-inflammatory effects induced by ABA do not requires Gi
protein activity. Our study reveals that the ABA/LANCL2 system is a powerful endogenous system regulating spinal
neuroinflammation and nociceptive processing, suggesting the potential utility of ABA as the management of
neuropathic pain.