Activating the vlPAG-LC neural pathway alleviates neuropathic pain and comorbid anxiety-like behaviors through distinct projections

The ventrolateral periaqueductal gray (vlPAG) functions as a critical hub in the descending pain modulatory system. The vlPAG receives and processes upstream pain information, which is involved in descending pain modulation through projecting downstream to rostroventral medulla (RVM) or locus coeruleus (LC). Although the modulatory roles of the upstream pathways and the vlPAG-RVM connection in neuropathic pain have been extensively studied, but the involvement of the vlPAG-LC neural pathway in regulating neuropathic pain and related comorbidity requires further investigation. In the present study, the excitability of the vlPAG-LC pathway was found to be increased in spared nerve injury (SNI) mice. Activating of the vlPAG-LC pathway using chemogenetic approach produced antinociceptive and anxiolytic effects in SNI mice. Intrathecal administration of α2-adrenergic receptor antagonist reversed analgesic effect of the vlPAG-LC pathway in SNI mice. However, the anxiolytic effect of this neural pathway was unaffected. A previously unrecognized vlPAG-LC-anterior cingulate cortex (ACC) tertiary pathway was identified in the current work. The excitability of ACC increased in SNI mice, whereas decreased following activation of the vlPAG-LC pathway. Activation of the ACC pyramidal neurons blocked the vlPAG-LC pathway-mediated anxiolytic effect but not analgesic effect in SNI mice. Furthermore, the anxiolytic effect of the vlPAG-LC pathway in SNI mice was altered after activation of the LC-ACC pathway or microinjection of norepinephrine into ACC. The present results underscored spinal dorsal horn and ACC as the potential downstream targets for analgesic and anxiolytic effects of the vlPAG-LC neural pathway in SNI mice, respectively.