title: Toll-like receptor 4 regulates chronic stress-induced visceral pain in mice.
abstract: BACKGROUND
  Functional gastrointestinal disorders, which have visceral hypersensitivity as a core symptom, are frequently comorbid with stress-related psychiatric disorders. Increasing evidence points to a key role for toll-like receptor 4 (TLR4) in chronic pain states of somatic origin. However, the central contribution of TLR4 in visceral pain sensation remains elusive.
  
  
  METHODS
  With pharmacological and genetic approaches, we investigated the involvement of TLR4 in the modulation of visceral pain. The TLR4-deficient and wild-type mice were exposed to chronic stress. Visceral pain was evaluated with colorectal distension. Protein expression levels for TLR4, Cd11b, and glial fibrillary acidic protein (glial cells markers) were quantified in the lumbar region of the spinal cord, prefrontal cortex (PFC), and hippocampus. To evaluate the effect of blocking TLR4 on visceral nociception, TAK-242, a selective TLR4 antagonist, was administered peripherally (intravenous) and centrally (intracerebroventricular and intra-PFC) (n = 10-12/experimental group).
  
  
  RESULTS
  The TLR4 deficiency reduced visceral pain and prevented the development of chronic psychosocial stress-induced visceral hypersensitivity. Increased expression of TLR4 coupled with enhanced glia activation in the PFC and increased levels of proinflammatory cytokines were observed after chronic stress in wild-type mice. Administration of a TLR4 specific antagonist, TAK-242, attenuated visceral pain sensation in animals with functional TLR4 when administrated centrally and peripherally. Moreover, intra-PFC TAK-242 administration also counteracted chronic stress-induced visceral hypersensitivity.
  
  
  CONCLUSIONS
  Our results reveal a novel role for TLR4 within the PFC in the modulation of visceral nociception and point to TLR4 as a potential therapeutic target for the development of drugs to treat visceral hypersensitivity.
authors: Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors: Monica
authors: M
authors: Tramullas
authors: School of Pharmacy, University College Cork, Cork, Ireland.
authors: Beate C
authors: BC
authors: Finger
authors: Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors: Rachel D
authors: RD
authors: Moloney
authors: Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors: Anna V
authors: AV
authors: Golubeva
authors: Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors: Gerard
authors: G
authors: Moloney
authors: Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry , University College Cork, Cork, Ireland.
authors: Timothy G
authors: TG
authors: Dinan
authors: Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. Electronic address: j.cryan@ucc.ie.
authors: John F
authors: JF
authors: Cryan
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002908:Chronic Disease; D004291:Dominance-Subordination; D005904:Glial Fibrillary Acidic Protein; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D008159:Lumbar Vertebrae; D008297:Male; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013315:Stress, Psychological / Q000150:complications* / Q000503:physiopathology; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059265:Visceral Pain / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology*
chemical_list: D000700:Analgesics; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D013449:Sulfonamides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; C528900:glial fibrillary astrocytic protein, mouse
keywords: Chronic stress; TLR4; microglia activation; prefrontal cortex; spinal cord; visceral hypersensitivity