Papers of the Week

The transition from acute to chronic pain results in maladaptive brain remodeling, as characterized by sensorial hypersensitivity and the ensuing appearance of emotional disorders. Using the chronic constriction injury of the sciatic nerve as a model of neuropathic pain in male Sprague-Dawley rats, we identified time-dependent plasticity of locus coeruleus (LC) neurons related to the site of injury, ipsilateral (LCipsi) or contralateral (LCcontra) to the lesion, hypothesizing that the LC->dorsal reticular nucleus (DRt) pathway is involved in the pathological nociception associated with chronic pain. LCipsi inactivation with lidocaine increased cold allodynia 2 days after nerve injury but not later. However, similar blockade of LCcontra reduced cold allodynia 7 and 30 days after inducing neuropathy but not earlier. Furthermore, lidocaine blockade of the LCipsi or LCcontra reversed pain-induced depression 30 days after neuropathy. Long-term pain enhances pCREB (phosphorylated cAMP-response element binding protein) expression in the DRtcontra but not in the DRtipsi. Moreover, inactivation of the LCcontra->DRtcontra pathway using dual viral-mediated gene transfer of DREADDs (designer receptor exclusively activated by designer drugs) produced consistent analgesia in evoked and spontaneous pain 30 days post-injury. This analgesia was similar to that produced by spinal activation of [alpha]2-adrenoreceptors. Furthermore, chemogenetic inactivation of the LCcontra->DRtcontra pathway induced depressive-like behaviour in naive animals but it did not modify long-term pain-induced depression. Overall, nerve damage activates the LCipsi, which temporally dampens the neuropathic phenotype. However, the ensuing activation of a LCcontra->DRtcontra facilitatory pain projection contributes to chronic pain, while global bilateral LC activation contributes to associated depressive-like phenotype.