The Effect of ABHD6 Inhibition on Pain-Induced Depressive Behaviors in Male and Female Mice

Over half of all individuals suffering from chronic neuropathic pain will also experience moderate to severe depression, known as chronic pain-induced depression (CPiD). However, there are no known effective treatments that alleviate both chronic pain and its resultant CPiD. Therefore, we used a partial sciatic nerve ligation (pSNL) model to cause permanent neuropathic pain in mice and monitored development of pain and depressive-like behaviors for 29 days. One group was treated with KT-182 (2mg/kg), an irreversible ABHD6 inhibitor, to increase 2-AG (an endocannabinoid) in dopaminergic neurons of the ventral tegmental area with the hypothesis that it will reduce depressive-like behaviors in CPiD-impacted mice; the control group was treated with vehicle. Around 71% of mice that underwent pSNL developed the expected neuropathic pain conditions as indicated by the Von Frey method of measuring mechanical allodynia by Day 7. 42% of mice exhibiting chronic pain also experienced depressive-like symptoms measured by Forced Swim Tests, indicating CPiD. KT-182 had an analgesic effect during days of dosing. Interestingly, the drug seemed to worsen depressive-like symptoms (p=0.024*) in treated female mice as compared to vehicle, but it did not impact depressive-like behaviors of the treated male mice. The complex mechanisms causing CPiD are partially explained by the 2-AG endocannabinoid, which upon increase may alleviate neuropathic pain symptoms. However, further work must be done to uncover the neural pathways implicated in pain-induced depression.