Resveratrol Engages AMPK to Attenuate ERK and mTOR Signaling in Sensory Neurons and Inhibits Incision-Induced Acute and Chronic Pain

Abstract

BackgroundDespite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK) may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors.ResultsTo test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6) is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE2 injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment.ConclusionsThese results highlight the importance of signaling to translation control in peripheral sensitization of nociceptors and provide further evidence for activation of AMPK as a novel treatment avenue for acute and chronic pain states.

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

“…It will be interesting to perform an unbiased, comparative assessment of differential downstream target engagement in neural stem cells following chronic rapamycin and metformin treatment. Finally, differences in the response of the IRS/Akt or Grb10 feedback loops ( pain by the simultaneous attenuation of both mTOR and ERK signaling (Melemedjian et al 2011;Tillu et al 2012). In contrast, we observe that both pharmacological and genetic inhibition of mTORC1 evokes spontaneous pain, mechanical hypersensitivity, and increased sensory neuron excitability (Melemedjian et al 2013).…”

A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors

“…7,74 Male Sprague-Dawley rats were anesthetized with isoflurane vaporized through a nose cone. The plantar aspect of the left hind paw was scrubbed with betadine and 70% alcohol 3 times.…”

AMPK activation prevents prenatal stress-induced cognitive impairment: Modulation of mitochondrial content and oxidative stress

“…Resveratrol (3,4 0 ,5 trihydroxystilbene, Res), a naturally occurring phytoalexin compound present in almost 70 plant species (such as grape, peanut, and soya beans), is considered one of the most effective known antioxidants. Similar to other chemical activators of AMPK, such as 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and metformin, Res has been widely accepted as a natural AMPK activator [20,21]. The impact of Res on the prevention of prenatal stress-induced cognitive impairment has been recently reported, but the exact mechanisms involved in its neuroprotective effects are still poorly characterized [22][23][24].…”