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

Abstract

Background and objectivesAMP-activated protein kinase (AMPK) activator drugs decrease hypersensitivity in mice with pain. This study examines if postsurgery treatment with the prototype AMPK activator metformin and a new mechanism-specific AMPK activator, O304, after plantar hindpaw incision in mice, would reduce mechanical hypersensitivity and produce changes in the AMPK pathway in the dorsal root ganglion (DRG).MethodsTo create postoperative pain, an incision was made in the left plantar hindpaw. Animals were randomized into four oral gavage drug treatment groups (n=8/group): (1) vehicle, (2) metformin 200 mg/kg, (3) O304 200 mg/kg and (4) O304 200 mg/kg plus metformin 200 mg/kg. Drug gavages were performed 4 hours postsurgery and were repeated for 3 days. Mechanical hypersensitivity was measured with von Frey filaments. Changes in phosphorylated AMP-activated protein kinase alpha subunit, phosphorylated mechanistic target of rapamycin and phosphorylated eukaryotic initiation factor 2 alpha in DRG neurons were examined by immunohistochemistry.ResultsO304 or metformin increased von Frey thresholds (reduced mechanical hypersensitivity) in plantar incision mice versus vehicle-treated incision mice between days 1 and 4 (difference of mean area under the curve, O304: 2.24 g*day; 95% CI of the difference 0.28 to 4.21, p=0.011; metformin: 2.56 g*day; 95% CI of the difference 1.71 to 3.41, p<0.001). The drug combination further elevated von Frey thresholds. In the vehicle-treated group, the AMP-activated protein kinase alpha subunit was downregulated and mechanistic target of rapamycin and eukaryotic initiation factor 2 alpha were upregulated in DRG neurons; these deficits were reversed by the AMPK activator treatments.ConclusionsEarly treatment with the mechanism-specific AMPK activator O304 or the prototype AMPK activator metformin reduces mechanical hypersensitivity in a postoperative pain model in mice. These drugs also normalize the AMPK pathway in the DRG.

What’s new in chronic pain pathophysiology

“…10,11 Mouse model studies have demonstrated that AMPK activation can reduce peripheral nerve injury and allodynia within 7 days of injury. 12 AMPK activators have also demonstrated complete resolution of long-standing nerve injury within 60 days of the event. One study looked at metformin and O304 in a postoperative pain mouse model and demonstrated reduced mechanical pain sensitivity with both agents compared with the drug vehicle.…”

“…This study also demonstrated an even greater synergistic effect with both agents co-administered. 12 There are rich opportunities for further study and expansion within this field. Metformin studies may be designed to evaluate treatment of postsurgical and neuropathic pain, possibly as part of a preemptive perioperative regimen such as an enhanced recovery after surgery protocol.…”

“…This study also demonstrated an even greater synergistic effect with both agents co-administered. 12 …”

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

“…We read with great interest your excellent paper on the antihyperalgesic effect of AMP-activated protein kinase (AMPK) activators 1. The fact that you assert that the value of the drug may be in the postsurgical period in patients with diabetic neuropathy caught our attention.…”

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

“…The goal of our published paper ‘Antihyperalgesia effect of AMP-activated protein kinase (AMPK) activators in a mouse model of postoperative pain’ was to find the analgesic efficacy of AMP-activated protein kinase activators in a postsurgical pain model and to evaluate the metabolic pathways by which AMPK activator drugs can modulate nociception 1. This might allow the reduction or elimination of opioids for postsurgical pain, a goal that anesthesiologists are striving for.…”