title: Histamine H4receptor agonist-induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress.
abstract: Neuropathic pain is under-treated, with a detrimental effect on quality of life, partly because of low treatment efficacy, but also because pathophysiological mechanisms are not fully elucidated. To clarify the pathobiology of neuropathic pain, we studied the contribution of neuroinflammation and oxidative stress in a model of peripheral neuropathy. We also assessed an innovative treatment for neuropathic pain by investigating the effects of histamine H4receptor ligands in this model.
  
  
  
  A peripheral mononeuropathy was induced in mice, by spared nerve injury (SNI). Neuroinflammation and oxidative stress parameters were evaluated by spectrophotometry. The mechanical (von Frey test) and thermal (plantar test) nociceptive thresholds were evaluated.
  
  
  
  SNI mice showed increased expression of the pro-inflammatory cytokines IL-1ß and TNF-α, decreased antioxidant enzyme Mn-containing SOD (MnSOD), increased levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), an indicator of oxidative DNA damage, and of PARP, nuclear enzyme activated upon DNA damage. Intrathecal administration of VUF 8430 (H4receptor agonist) reversed the mechanical and thermal allodynia and was associated with decreased expression of IL-1ß, TNF-α, 8-OHdG and PARP and with restoration of MnSOD activity in the spinal cord and sciatic nerve. These effects were prevented by JNJ 10191584 (H4receptor antagonist).
  
  
  
  In the SNI mouse model of neuropathic pain, neuronal H4receptor stimulation counteracts hyperalgesia and reduces neuroinflammation and oxidative stress in the spinal cord and sciatic nerve. Targeting both oxidative stress and pro-neuroinflammatory pathways through H4receptor-mediated mechanisms could have promising therapeutic potential for neuropathic pain management.
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Sanna
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lucarini
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: Mariaconcetta
authors.initials: M
authors.lastname: Durante
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Galeotti
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology*; D006632:Histamine / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D006146:Guanidines; C498829:Hrh4 protein, mouse; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C516215:S-(2-guanidylethyl)isothiourea; D006632:Histamine; D013890:Thiourea