Post-surgical pain represents an important clinical problem that is a major cause of chronic pain and a burden on healthcare systems. Treatments that target molecular events that underlie post-surgical acute and chronic pain may offer better management of post-surgical pain and reduce the proportion of patients (as high as 50%) that develop chronic pain after surgey. The focus of this research effort is to further develop two potential mechanisms for the pharmacological manipulation of pain: adenosine monophosphate activated kinase (AMPK) activators and peptides that disrupt voltage-gated sodium channel type 1.7 (Nav1.7) / extracellular signal regulated kinase (ERK) interactions. AMPK is an energy sensing kinase that endogenously regulates cellular pathways involved in growth and proliferation and emerging evidence suggests that activation of AMPK decreases the excitability of neurons. We have demonstrated that diverse AMPK activators prevent and reverse post-surgical pain via inhibition of mammalian target of rapamycin (mTOR) and ERK signaling pathways. Moreover, AMPK activators inhibit excitability and evoked hyperexcitability of sensory neurons. Nav1.7 is expressed primarily in the peripheral nervous system and plays an important role in setting the excitability of the neuron. Human genetic studies have demonstrated a crucial role for Nav1.7 in pain processing and recent evidence suggests that Nav1.7 also plays an important role in acquired pain disorders yet mechanisms through which Nav1.7 is regulated are only now coming into focus. Our preliminary data strongly suggest that AMPK activators are linked to interference with ERK mediated phosphorylation of Nav1.7. This process decreases the excitability of sensory neurons and reduces hyperexcitability induced by algogens linked to post-surgical pain. The goal of this proposal is to test the hypothesis that AMPK activators represent a new therapeutic avenue for the treatment of post-surgical pain through aims examining: 1) the pharmacology of AMPK activators in behavioral models of post-surgical pain, 2) mechanisms of AMPK regulation of mTOR and ERK in sensory neurons and 3) AMPK-mediated regulation of ERK interactions with Nav1.7. We anticipate developing a rationale for two novel therapeutic avenues for the treatment of pain under this proposal: 1) AMPK activators and 2) peptides that disrupt ERK/Nav1.7 interactions. Hence, the present application will utilize a multidisciplinary approach to tackle the problem of post-surgical pain with the goal of advancing novel therapies toward the clinic.
Post-surgical pain is a major clinical problem requiring novel treatment approaches. Experiments described herein have the potential to lead to the development of novel therapeutics for the treatment of post-surgical pain that directly target mechanisms that promote pain after surgery.
|Ray, Pradipta; Torck, Andrew; Quigley, Lilyana et al. (2018) Comparative transcriptome profiling of the human and mouse dorsal root ganglia: an RNA-seq-based resource for pain and sensory neuroscience research. Pain 159:1325-1345|
|Price, Theodore J; Gold, Michael S (2018) From Mechanism to Cure: Renewing the Goal to Eliminate the Disease of Pain. Pain Med 19:1525-1549|
|Megat, Salim; Shiers, Stephanie; Moy, Jamie K et al. (2018) A Critical Role for Dopamine D5 Receptors in Pain Chronicity in Male Mice. J Neurosci 38:379-397|
|Barragán-Iglesias, Paulino; Lou, Tzu-Fang; Bhat, Vandita D et al. (2018) Inhibition of Poly(A)-binding protein with a synthetic RNA mimic reduces pain sensitization in mice. Nat Commun 9:10|
|Burton, Michael D; Tillu, Dipti V; Mazhar, Khadijah et al. (2017) Pharmacological activation of AMPK inhibits incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming in mice. Neuroscience 359:119-129|
|Asiedu, Marina N; Han, Chongyang; Dib-Hajj, Sulayman D et al. (2017) The AMPK Activator A769662 Blocks Voltage-Gated Sodium Channels: Discovery of a Novel Pharmacophore with Potential Utility for Analgesic Development. PLoS One 12:e0169882|
|Moy, Jamie K; Khoutorsky, Arkady; Asiedu, Marina N et al. (2017) The MNK-eIF4E Signaling Axis Contributes to Injury-Induced Nociceptive Plasticity and the Development of Chronic Pain. J Neurosci 37:7481-7499|
|Asiedu, Marina N; Dussor, Gregory; Price, Theodore J (2016) Targeting AMPK for the Alleviation of Pathological Pain. Exp Suppl 107:257-285|
|Pember, Stephen O; Mejia, Galo L; Price, Theodore J et al. (2016) Piperidinyl thiazole isoxazolines: A new series of highly potent, slowly reversible FAAH inhibitors with analgesic properties. Bioorg Med Chem Lett 26:2965-2973|
|Price, Theodore J; Das, Vaskar; Dussor, Gregory (2016) Adenosine Monophosphate-activated Protein Kinase (AMPK) Activators For the Prevention, Treatment and Potential Reversal of Pathological Pain. Curr Drug Targets 17:908-20|
Showing the most recent 10 out of 34 publications