PMID- 31335645
OWN - NLM
STAT- MEDLINE
DCOM- 20200505
LR  - 20240229
IS  - 1872-6623 (Electronic)
IS  - 0304-3959 (Print)
IS  - 0304-3959 (Linking)
VI  - 160
IP  - 8
DP  - 2019 Aug
TI  - An NPY Y1 receptor antagonist unmasks latent sensitization and reveals the 
      contribution of protein kinase A and Epac to chronic inflammatory pain.
PG  - 1754-1765
LID - 10.1097/j.pain.0000000000001557 [doi]
AB  - Peripheral inflammation produces a long-lasting latent sensitization of spinal 
      nociceptive neurons, that is, masked by tonic inhibitory controls. We explored 
      mechanisms of latent sensitization with an established four-step approach: (1) 
      induction of inflammation; (2) allow pain hypersensitivity to resolve; (3) 
      interrogate latent sensitization with a channel blocker, mutant mouse, or 
      receptor antagonist; and (4) disrupt compensatory inhibition with a receptor 
      antagonist so as to reinstate pain hypersensitivity. We found that the 
      neuropeptide Y Y1 receptor antagonist BIBO3304 reinstated pain hypersensitivity, 
      indicative of an unmasking of latent sensitization. BIBO3304-evoked reinstatement 
      was not observed in AC1 knockout mice and was prevented with intrathecal 
      co-administration of a pharmacological blocker to the N-methyl-D-aspartate 
      receptor (NMDAR), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), 
      transient receptor potential cation channel A1 (TRPA1), channel V1 (TRPV1), or 
      exchange protein activated by cAMP (Epac1 or Epac2). A PKA activator evoked both 
      pain reinstatement and touch-evoked pERK expression in dorsal horn; the former 
      was prevented with intrathecal co-administration of a TRPA1 or TRPV1 blocker. An 
      Epac activator also evoked pain reinstatement and pERK expression. We conclude 
      that PKA and Epac are sufficient to maintain long-lasting latent sensitization of 
      dorsal horn neurons that is kept in remission by the NPY-Y1 receptor system. 
      Furthermore, we have identified and characterized 2 novel molecular signaling 
      pathways in the dorsal horn that drive latent sensitization in the setting of 
      chronic inflammatory pain: NMDAR-->AC1-->PKA-->TRPA1/V1 and NMDAR-->AC1-->Epac1/2. New 
      treatments for chronic inflammatory pain might either increase endogenous NPY 
      analgesia or inhibit AC1, PKA, or Epac.
FAU - Fu, Weisi
AU  - Fu W
AD  - Department of Physiology, University of Kentucky Medical Center, Lexington, KY, 
      United States.
FAU - Nelson, Tyler S
AU  - Nelson TS
AD  - Department of Anesthesiology and Perioperative Medicine, Pittsburgh Center for 
      Pain Research, and Pittsburgh Project to End Opioid Misuse, University of 
      Pittsburgh, Pittsburgh, PA, United States.
AD  - Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States.
AD  - Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, 
      PA, United States.
FAU - Santos, Diogo F
AU  - Santos DF
AD  - Department of Anesthesiology and Perioperative Medicine, Pittsburgh Center for 
      Pain Research, and Pittsburgh Project to End Opioid Misuse, University of 
      Pittsburgh, Pittsburgh, PA, United States.
FAU - Doolen, Suzanne
AU  - Doolen S
AD  - Department of Anesthesiology and Perioperative Medicine, Pittsburgh Center for 
      Pain Research, and Pittsburgh Project to End Opioid Misuse, University of 
      Pittsburgh, Pittsburgh, PA, United States.
FAU - Gutierrez, Javier J P
AU  - Gutierrez JJP
AD  - Department of Anesthesiology and Perioperative Medicine, Pittsburgh Center for 
      Pain Research, and Pittsburgh Project to End Opioid Misuse, University of 
      Pittsburgh, Pittsburgh, PA, United States.
FAU - Ye, Na
AU  - Ye N
AD  - Department of Pharmacology and Toxicology, University of Texas Medical Branch, 
      Galveston, TX, United States.
FAU - Zhou, Jia
AU  - Zhou J
AD  - Department of Pharmacology and Toxicology, University of Texas Medical Branch, 
      Galveston, TX, United States.
FAU - K Taylor, Bradley
AU  - K Taylor B
AD  - Department of Physiology, University of Kentucky Medical Center, Lexington, KY, 
      United States.
AD  - Department of Anesthesiology and Perioperative Medicine, Pittsburgh Center for 
      Pain Research, and Pittsburgh Project to End Opioid Misuse, University of 
      Pittsburgh, Pittsburgh, PA, United States.
AD  - Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States.
LA  - eng
GR  - T32 NS073548/NS/NINDS NIH HHS/United States
GR  - R01 DA037621/DA/NIDA NIH HHS/United States
GR  - R01 NS062306/NS/NINDS NIH HHS/United States
GR  - R01 NS045954/NS/NINDS NIH HHS/United States
GR  - K02 DA019656/DA/NIDA NIH HHS/United States
GR  - KL2 TR000116/TR/NCATS NIH HHS/United States
GR  - K01 DA031961/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Pain
JT  - Pain
JID - 7508686
RN  - 0 (Epac protein, mouse)
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 0 (Receptors, Neuropeptide Y)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - O35HK034KO (BIBO 3304)
SB  - IM
MH  - Animals
MH  - Arginine/*analogs & derivatives/pharmacology
MH  - Chronic Pain/*metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/*metabolism
MH  - Guanine Nucleotide Exchange Factors/*metabolism
MH  - Hyperalgesia/*metabolism
MH  - Inflammation/*metabolism
MH  - Male
MH  - Mice
MH  - Pain Measurement
MH  - Pain Threshold/drug effects
MH  - Phosphorylation/drug effects
MH  - Receptors, Neuropeptide Y/*antagonists & inhibitors
PMC - PMC6903783
MID - NIHMS1523293
EDAT- 2019/07/25 06:00
MHDA- 2020/05/06 06:00
PMCR- 2020/08/01
CRDT- 2019/07/24 06:00
PHST- 2019/07/24 06:00 [entrez]
PHST- 2019/07/25 06:00 [pubmed]
PHST- 2020/05/06 06:00 [medline]
PHST- 2020/08/01 00:00 [pmc-release]
AID - 00006396-201908000-00010 [pii]
AID - 10.1097/j.pain.0000000000001557 [doi]
PST - ppublish
SO  - Pain. 2019 Aug;160(8):1754-1765. doi: 10.1097/j.pain.0000000000001557.