PMID- 23292683
OWN - NLM
STAT- MEDLINE
DCOM- 20130322
LR  - 20231213
IS  - 1546-1726 (Electronic)
IS  - 1097-6256 (Print)
IS  - 1097-6256 (Linking)
VI  - 16
IP  - 2
DP  - 2013 Feb
TI  - Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(-) 
      homeostasis.
PG  - 183-92
LID - 10.1038/nn.3295 [doi]
AB  - A major unresolved issue in treating pain is the paradoxical hyperalgesia 
      produced by the gold-standard analgesic morphine and other opiates. We found that 
      hyperalgesia-inducing treatment with morphine resulted in downregulation of the 
      K(+)-Cl(-) co-transporter KCC2, impairing Cl(-) homeostasis in rat spinal lamina 
      l neurons. Restoring the anion equilibrium potential reversed the 
      morphine-induced hyperalgesia without affecting tolerance. The hyperalgesia was 
      also reversed by ablating spinal microglia. Morphine hyperalgesia, but not 
      tolerance, required mu opioid receptor-dependent expression of P2X4 receptors 
      (P2X4Rs) in microglia and mu-independent gating of the release of brain-derived 
      neurotrophic factor (BDNF) by P2X4Rs. Blocking BDNF-TrkB signaling preserved 
      Cl(-) homeostasis and reversed the hyperalgesia. Gene-targeted mice in which Bdnf 
      was deleted from microglia did not develop hyperalgesia to morphine. However, 
      neither morphine antinociception nor tolerance was affected in these mice. Our 
      findings dissociate morphine-induced hyperalgesia from tolerance and suggest the 
      microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target for preventing 
      hyperalgesia without affecting morphine analgesia.
FAU - Ferrini, Francesco
AU  - Ferrini F
AD  - Institut Universitaire en Sante Mentale de Quebec, Quebec, Canada.
FAU - Trang, Tuan
AU  - Trang T
FAU - Mattioli, Theresa-Alexandra M
AU  - Mattioli TA
FAU - Laffray, Sophie
AU  - Laffray S
FAU - Del'Guidice, Thomas
AU  - Del'Guidice T
FAU - Lorenzo, Louis-Etienne
AU  - Lorenzo LE
FAU - Castonguay, Annie
AU  - Castonguay A
FAU - Doyon, Nicolas
AU  - Doyon N
FAU - Zhang, Wenbo
AU  - Zhang W
FAU - Godin, Antoine G
AU  - Godin AG
FAU - Mohr, Daniela
AU  - Mohr D
FAU - Beggs, Simon
AU  - Beggs S
FAU - Vandal, Karen
AU  - Vandal K
FAU - Beaulieu, Jean-Martin
AU  - Beaulieu JM
FAU - Cahill, Catherine M
AU  - Cahill CM
FAU - Salter, Michael W
AU  - Salter MW
FAU - De Koninck, Yves
AU  - De Koninck Y
LA  - eng
GR  - 134759-1/CAPMC/CIHR/Canada
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130106
PL  - United States
TA  - Nat Neurosci
JT  - Nature neuroscience
JID - 9809671
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (CD11b Antigen)
RN  - 0 (Chlorides)
RN  - 0 (Narcotic Antagonists)
RN  - 0 (Narcotics)
RN  - 0 (P2rx4 protein, mouse)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (Receptors, Purinergic P2X4)
RN  - 0 (Ribosome Inactivating Proteins, Type 1)
RN  - 0 (Symporters)
RN  - 36B82AMQ7N (Naloxone)
RN  - 76I7G6D29C (Morphine)
RN  - EC 3.2.2.22 (Saporins)
SB  - IM
CIN - Nat Rev Neurosci. 2013 Mar;14(3):154. PMID: 23340603
MH  - Animals
MH  - Biophysical Phenomena/drug effects/genetics
MH  - Brain-Derived Neurotrophic Factor/genetics/metabolism
MH  - CD11b Antigen/genetics/metabolism
MH  - Chlorides/*metabolism
MH  - Down-Regulation/drug effects
MH  - Gene Expression Regulation/drug effects
MH  - Homeostasis/*drug effects
MH  - Hot Temperature/adverse effects
MH  - Hyperalgesia/*drug therapy
MH  - Ion Channel Gating/drug effects
MH  - Male
MH  - Membrane Potentials/drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Microglia/*drug effects/physiology
MH  - Morphine/*administration & dosage
MH  - Motor Activity/drug effects
MH  - Naloxone/pharmacology
MH  - Narcotic Antagonists/pharmacology
MH  - Narcotics/*administration & dosage
MH  - Neurons/*drug effects
MH  - Pain Threshold/drug effects
MH  - Patch-Clamp Techniques
MH  - Protein Synthesis Inhibitors/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Purinergic P2X4/genetics/metabolism
MH  - Ribosome Inactivating Proteins, Type 1/pharmacology
MH  - Rotarod Performance Test
MH  - Saporins
MH  - Signal Transduction/drug effects/genetics
MH  - Spinal Cord/cytology
MH  - Symporters/metabolism
MH  - Time Factors
MH  - Touch
MH  - Vocalization, Animal/drug effects
MH  - K Cl- Cotransporters
PMC - PMC4974077
MID - CAMS3888
OID - NLM: CAMS3888
COIS- COMPETING FINANCIAL INTERESTS The authors declare no competing financial 
      interests.
EDAT- 2013/01/08 06:00
MHDA- 2013/03/23 06:00
PMCR- 2016/08/04
CRDT- 2013/01/08 06:00
PHST- 2012/10/08 00:00 [received]
PHST- 2012/12/05 00:00 [accepted]
PHST- 2013/01/08 06:00 [entrez]
PHST- 2013/01/08 06:00 [pubmed]
PHST- 2013/03/23 06:00 [medline]
PHST- 2016/08/04 00:00 [pmc-release]
AID - nn.3295 [pii]
AID - 10.1038/nn.3295 [doi]
PST - ppublish
SO  - Nat Neurosci. 2013 Feb;16(2):183-92. doi: 10.1038/nn.3295. Epub 2013 Jan 6.