Pharmacological activation of AMPK inhibits incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming in mice

Abstract

New therapeutics to manage post-surgical pain are needed to mitigate the liabilities of opioid and other analgesics. Our previous work shows that key modulators of excitability in peripheral nociceptors, such as extracellular signal-regulated kinases (ERK) are inhibited by activation of adenosine monophosphate activated protein kinase (AMPK). We hypothesized that AMPK activation would attenuate acute incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming caused by surgery in mice. Here we have used a variety of administration routes and combinations of AMPK activators to test this hypothesis. Topical administration of a resveratrol-based cream inhibited acute mechanical hypersensitivity evoked by incision and blocked the development of hyperalgesic priming. We also observed that systemic administration of metformin dose-dependently inhibited incision-evoked mechanical hypersensitivity and hyperalgesic priming. Interestingly, low doses of systemic metformin and local resveratrol that had no acute effect were able to mitigate development of hyperalgesic priming. Combined treatment with doses of systemic metformin and local resveratrol that were not effective on their own enhanced the acute efficacy of the individual AMPK activators for post-surgical mechanical pain alleviation and blocked the development of hyperalgesic priming. Finally, we used dorsal root ganglion (DRG) neurons in culture to show that resveratrol and metformin given in combination shift the concentration-response curve for AMPK activation to the left and increase the magnitude of AMPK activation. Therefore, we find that topical administration is an effective treatment route of administration and combining systemic and local treatments led to anti-nociceptive efficacy in acute mechanical hypersensitivity at doses that were not effective alone. Collectively our work demonstrates a specific effect of AMPK activators on post-surgical pain and points to novel therapeutic opportunities with potential immediate impact in the clinical setting.

Antihyperalgesia effect of AMP-activated protein kinase (AMPK) activators in a mouse model of postoperative pain

“…The distribution of the primary outcome was evaluated for normality using the Shapiro-Wilk test and for homogeneity of variance using the Levene test. The primary outcome of the study, the area under the curve (AUC) of the von Frey force thresholds over time (gram*day) between postoperative days 1-4, was compared between the four groups using the The sample size for demonstrating that metformin elevated von Frey thresholds in postoperative incision pain mice versus vehicle-treated incision mice over the postoperative period was obtained from Burton et al 3 in the plantar incision model, in which metformin 200 mg/kg administered starting 2 days presurgery and continued through 1 day postsurgery showed elevated von Frey thresholds compared with vehicle-treated mice. That mouse study had five groups, with n=6 per group, and so we chose n=8 per group for our behavioral study.…”

“…2 A previous plantar incision pain study in mice demonstrated that the prototype AMPK activator drug metformin 200 mg/kg administered preemptively starting 2 days presurgery and continued through 1 day postsurgery reduced postoperative mechanical hypersensitivity. 3 Although the primary mode of AMPK activation with metformin is inhibition of complex 1 of the mitochondrial respiratory chain and suppression of ATP production, 1 2 4 metformin can activate AMPK through multiple indirect mechanisms. [3][4][5][6] In addition, metformin has other activities not involving AMPK, 4 7 and that may contribute to its antihyperalgesic activity in mice.…”

“…3 Although the primary mode of AMPK activation with metformin is inhibition of complex 1 of the mitochondrial respiratory chain and suppression of ATP production, 1 2 4 metformin can activate AMPK through multiple indirect mechanisms. [3][4][5][6] In addition, metformin has other activities not involving AMPK, 4 7 and that may contribute to its antihyperalgesic activity in mice. Metformin is derived from a natural product used in herbal medicine and was not designed to target a specific pathway.…”

Metformin prevents colonic barrier dysfunction by inhibiting mast cell activation in maternal separation‐induced IBS‐like rats

“…Studies have demonstrated that metformin attenuates inflammatory hyperalgesia, 15 incision-evoked mechanical hypersensitivity, and hyperalgesia. 16 Bullón et al also demonstrated that the administration of metformin improves clinical symptoms (eg, pain, fatigue, depression, and disturbed sleep) in patients with fibromyalgia. 17 Furthermore, metformin reduces serum cytokine levels, especially IL-6, to relieve chronic low-grade inflammation in women with polycystic ovary syndrome 18 and non-diabetic cohorts.…”

“…Metformin, a biguanide, is a first‐line treatment for type 2 diabetes mellitus and is used as an oral glucose‐lowering drug. Studies have demonstrated that metformin attenuates inflammatory hyperalgesia, incision‐evoked mechanical hypersensitivity, and hyperalgesia . Bullón et al also demonstrated that the administration of metformin improves clinical symptoms (eg, pain, fatigue, depression, and disturbed sleep) in patients with fibromyalgia .…”