The locus coeruleus (LC) noradrenergic (NA) neurons regulate pain and depression through their projections to various downstream nuclei. Although GABAergic (GABA) neurons in and near the LC (LC-GABA neurons) provide inhibitory synaptic inputs to LC-NA neurons, it remains unknown whether they are implicated in neuropathic pain and comorbid depression through LC-NA neurons. This study demonstrates that LC-GABA neurons respond to noxious stimuli with enhanced activity, and stimulation of these neurons elevates pain thresholds and exerts an anti-depressant-like effect in naive and neuropathic pain mice. Conversely, inhibition of LC-GABA neurons leads to hyperalgesia and depression-like behaviors in naive mice and exacerbates existing pain- and depression-like behaviors in neuropathic pain mice. Although LC-GABA neurons inhibit pain responses in LC-NA neurons, they modulate pain thresholds and depression-like behaviors in a manner independent of LC-NA neurons. In contrast, the projection from LC-GABA neurons to the ventrolateral periaqueductal gray (vlPAG) is enhanced, and stimulation of this projection mimics that of LC-GABA neurons conferring analgesic- and antidepressant-like effects. This study reveals the enhancement of the LCGABA-vlPAGGABA projection as a compensatory mechanism in neuropathic pain and suggests that further augmentation of this projection may be a therapeutic strategy for the treatment of comorbid neuropathic pain and depression.