PMID- 31650090
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2452-073X (Electronic)
IS  - 2452-073X (Linking)
VI  - 6
DP  - 2019 Aug-Dec
TI  - Alleviation of paclitaxel-induced mechanical hypersensitivity and hyperalgesic 
      priming with AMPK activators in male and female mice.
PG  - 100037
LID - 10.1016/j.ynpai.2019.100037 [doi]
LID - 100037
AB  - 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.
CI  - (c) 2019 The Author(s).
FAU - Inyang, Kufreobong E
AU  - Inyang KE
AD  - University of Texas at Dallas, School of Behavioral and Brain Sciences and Center 
      for Advanced Pain Studies, United States.
FAU - McDougal, Timothy A
AU  - McDougal TA
AD  - University of Texas at Dallas, School of Behavioral and Brain Sciences and Center 
      for Advanced Pain Studies, United States.
FAU - Ramirez, Eric D
AU  - Ramirez ED
AD  - University of Texas at Dallas, School of Behavioral and Brain Sciences and Center 
      for Advanced Pain Studies, United States.
FAU - Williams, Marisa
AU  - Williams M
AD  - University of Texas at Dallas, School of Behavioral and Brain Sciences and Center 
      for Advanced Pain Studies, United States.
FAU - Laumet, Geoffroy
AU  - Laumet G
AD  - MD Anderson Cancer Center, Department of Symptom Research, United States.
FAU - Kavelaars, Annemieke
AU  - Kavelaars A
AD  - MD Anderson Cancer Center, Department of Symptom Research, United States.
FAU - Heijnen, Cobi J
AU  - Heijnen CJ
AD  - MD Anderson Cancer Center, Department of Symptom Research, United States.
FAU - Burton, Michael
AU  - Burton M
AD  - University of Texas at Dallas, School of Behavioral and Brain Sciences and Center 
      for Advanced Pain Studies, United States.
FAU - Dussor, Gregory
AU  - Dussor G
AD  - University of Texas at Dallas, School of Behavioral and Brain Sciences and Center 
      for Advanced Pain Studies, United States.
FAU - Price, Theodore J
AU  - Price TJ
AD  - University of Texas at Dallas, School of Behavioral and Brain Sciences and Center 
      for Advanced Pain Studies, United States.
LA  - eng
GR  - R01 NS065926/NS/NINDS NIH HHS/United States
GR  - R01 NS073939/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20190927
PL  - United States
TA  - Neurobiol Pain
JT  - Neurobiology of pain (Cambridge, Mass.)
JID - 101705141
PMC - PMC6804652
OTO - NOTNLM
OT  - AMPK
OT  - CIPN
OT  - MK8722
OT  - Metformin
OT  - Narciclasine
OT  - Pain
COIS- The authors declare that they have no known competing financial interests or 
      personal relationships that could have appeared to influence the work reported in 
      this paper.
EDAT- 2019/10/28 06:00
MHDA- 2019/10/28 06:01
PMCR- 2019/09/27
CRDT- 2019/10/26 06:00
PHST- 2019/08/21 00:00 [received]
PHST- 2019/09/23 00:00 [revised]
PHST- 2019/09/25 00:00 [accepted]
PHST- 2019/10/26 06:00 [entrez]
PHST- 2019/10/28 06:00 [pubmed]
PHST- 2019/10/28 06:01 [medline]
PHST- 2019/09/27 00:00 [pmc-release]
AID - S2452-073X(19)30012-1 [pii]
AID - 100037 [pii]
AID - 10.1016/j.ynpai.2019.100037 [doi]
PST - epublish
SO  - Neurobiol Pain. 2019 Sep 27;6:100037. doi: 10.1016/j.ynpai.2019.100037. 
      eCollection 2019 Aug-Dec.