Right posterior insular epidural stimulation in rats with neuropathic pain induces a frequency-dependent and opioid system-mediated reduction of pain and its comorbid anxiety and depression

Neuropathic pain (NP) is a sensory, emotional, and persistent disturbing experience caused by a lesion or disease of the somatosensory system which can lead when chronic to comorbidities such as anxiety and depression. Available treatments (pharmacotherapy, neurostimulation) have partial and unpredictable response; therefore, it seems necessary to find a new therapeutical approach that could alleviate most related symptoms and improve patients 'emotional state'. Posterior Insula seems to be a potential target of neurostimulation for pain relief. However, its effects on pain-related anxiety and depression remain unknown. Using rats with spared nerve injury (SNI), this study aims to elucidate the correlation between NP and anxio-depressive disorders, evaluate potential analgesic, anxiolytic, and antidepressant effects of right posterior insula stimulation (IS) using low (LF-IS, 50 Hz) or high (HF-IS, 150 Hz) frequency and assess endogenous opioid involvement in these effects. Results showed positive correlation between NP, anxiety, and depression. LF-IS reversed anhedonia and despair-like behavior through pain alleviation, whereas HF-IS only reduced anhedonia, all effects involving endogenous opioids. These findings support the link between NP and anxio-depressive disorders. Moreover, IS appears to have analgesic, anxiolytic and antidepressant effects mediated by the endogenous opioid system, making it a promising target for neurostimulation.