Alleviation of paclitaxel-induced mechanical hypersensitivity and hyperalgesic priming with AMPK activators in male and female mice.

AMP-activated protein kinase (AMPK) is an energy-sensing kinase that has emerged as a novel therapeutic target for pain due to its ability to inhibit mechanistic target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) signaling, two signaling pathways that are linked to pain promotion after injury as well as the development of hyperalgesic priming. MAPK and mTOR signaling are also implicated in chemotherapy induced peripheral neuropathy (CIPN). We conducted a series of experiments to gain further insight into how AMPK activators might best be used to treat pain in both sexes in the setting of CIPN from paclitaxel. We also assessed whether hyperalgesic priming emerges from paclitaxel treatment and if this can be prevented by AMPK targeting. AMPK can be pharmacologically activated indirectly through regulation of upstream kinases like liver kinase B1 (LKB1) or directly using positive allosteric modulators. We used the indirect AMPK activators metformin and narciclasine, both of which have been shown to reduce pain in preclinical models but with much different potencies and different efficacies depending on the sex of the animal. We used the direct AMPK activator MK8722 because it is the most potent and specific such activator described to date. Here, the AMPK activators were used in 2 different treatment paradigms. First the drugs were given concurrently with paclitaxel to test whether they prevent mechanical hypersensitivity. Second the AMPK activators were given after the completion of paclitaxel treatment to test whether they reverse established mechanical hypersensitivity. Consistent with our previously published findings with metformin, narciclasine (1 mg/kg) produced an anti-hyperalgesic effect, preventing paclitaxel-induced neuropathy in outbred mice of both sexes. In contrast to metformin, narciclasine also reversed mechanical hypersensitivity in established CIPN. Both metformin (200 mg/kg) and narciclasine prevented the development of hyperalgesic priming induced by paclitaxel treatment. MK8722 (30 mg/kg) had no effect on mechanical hypersensitivity caused by paclitaxel in either the prevention or reversal treatment paradigms. However, MK8722 did attenuate hyperalgesic priming in male and female mice. We conclude that paclitaxel induces robust hyperalgesic priming that is prevented by AMPK targeting and that narciclasine is a particularly attractive candidate for further development as a CIPN treatment.