title: Stress in the adult rat exacerbates muscle pain induced by early-life stress.
abstract: BACKGROUND
  Early-life stress and exposure to stressful stimuli play a major role in the development of chronic widespread pain in adults. However, how they interact in chronic pain syndromes remains unclear.
  
  
  METHODS
  Dams and neonatal litters were submitted to a restriction of nesting material (neonatal limited bedding [NLB]) for 1 week. As adults, these rats were exposed to a painless sound stress protocol. The involvement of sympathoadrenal catecholamines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) in nociception was evaluated through behavioral and enzyme-linked immunosorbent assays, surgical interventions, and intrathecal antisense treatments.
  
  
  RESULTS
  Adult NLB rats exhibited mild muscle hyperalgesia, which was markedly aggravated by sound stress (peaking 15 days after exposure). Adrenal medullectomy did not modify hyperalgesia in NLB rats but prevented its aggravation by sound stress. Sustained administration of epinephrine to NLB rats mimicked sound stress effect. Intrathecal treatment with antisense directed to IL-6 receptor subunit gp130 (gp130), but not to tumor necrosis factor receptor type 1 (TNFR1), inhibited hyperalgesia in NLB rats. However, antisense against either gp130 or TNFR1 inhibited sound stress-induced enhancement of hyperalgesia. Compared with control rats, NLB rats exhibit increased plasma levels of IL-6 but decreased levels of TNFα, whereas sound stress increases IL-6 plasma levels in control rats but not in NLB rats.
  
  
  CONCLUSIONS
  Early-life stress induces a persistent elevation of IL-6, hyperalgesia, and susceptibility to chronic muscle pain, which is unveiled by exposure to stress in adults. This probably depends on an interaction between adrenal catecholamines and proinflammatory cytokines acting at muscle nociceptor level.
authors.affiliation: Departments of Oral and Maxillofacial Surgery, University of California at San Francisco, San Francisco, California; Division of Neuroscience, University of California at San Francisco, San Francisco, California.
authors.forename: Pedro
authors.initials: P
authors.lastname: Alvarez
authors.forename: Paul G
authors.initials: PG
authors.lastname: Green
authors.forename: Jon D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D000161:Acoustic Stimulation; D061605:Administration, Intravenous; D000315:Adrenalectomy; D000818:Animals; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000502:physiology*; D004837:Epinephrine / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006930:Hyperalgesia / Q000150:complications / Q000235:genetics / Q000503:physiopathology* / Q000601:surgery; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D063806:Myalgia / Q000150:complications / Q000503:physiopathology* / Q000601:surgery; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D011247:Pregnancy; D051381:Rats; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000502:physiology*; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015850:Interleukin-6; D020319:Oligodeoxyribonucleotides, Antisense; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D050822:Cytokine Receptor gp130; D004837:Epinephrine
keywords: IL-6; TNFα; myalgia; neonatal limited bedding; nociceptors; sound stress