PCC0208009, an indirect IDO1 inhibitor, alleviates neuropathic pain and co-morbidities by regulating synaptic plasticity of ACC and amygdala

Abstract

Background and purposeIndoleamine 2, 3-dioxygenase 1 (IDO1) has been linked to neuropathic pain and IDO1 inhibitors have been shown to reduce pain in animals. Some studies have indicated that IDO1 expression increased after neuropathic pain in hippocampus and spinal cord, whether these changes existing in anterior cingulate cortex (ACC) and amygdala remains obscure and how IDO1 inhibition leads to analgesia is largely unknown. Here, we evaluated the antinociceptive effect of PCC0208009, an indirect IDO1 inhibitor, on neuropathic pain and examined the related neurobiological mechanisms. Experimental approachThe effects of PCC0208009 on pain, cognition and anxiogenic behaviors were evaluated in a rat model of neuropathic pain. Motor disorder, sedation and somnolence were also assessed. Biochemical techniques were used to measure IDO1-mediated signaling changes in ACC and amygdala. Key resultsIn rats receiving spinal nerve ligation (SNL), IDO1 expression level was increased in ACC and amygdala. PCC0208009 attenuated pain-related behaviors in the formalin test and SNL model and increased cognition and anxiogenic behaviors in SNL rats at doses that did not affect locomotor activity and sleeping. PCC0208009 inhibited IDO1 expression in ACC and amygdala by inhibiting the IL-6-JAK2/STAT3-IDO1-GCN2-IL-6 pathway. In addition, PCC0208009 reversed synaptic plasticity at the functional and structural levels by suppressing NMDA2B receptor and CDK5/MAP2 or CDK5/Tau pathway in ACC and amygdala. Conclusion and implicationsThese results support the role of IDO1-mediated molecular mechanisms in neuropathic pain and suggest that the IDO1 inhibitor PCC0208009 demonstrates selective pain suppression and could be a useful pharmacological therapy for neuropathic pain.