title: The anti-hyperalgesic and anti-inflammatory profiles of p-cymene: Evidence for the involvement of opioid system and cytokines.
abstract: BACKGROUND
  Pain corresponds to the most frequent reason for visits to physicians, and its control by conventional drugs is accompanied by several side effects, making treatment difficult. For this reason, new chemical entities derived from natural products still hold great promise for the future of drug discovery to pain treatment.
  
  
  OBJECTIVE
  The objective of this study was to evaluate the antinociceptive and anti-inflammatory profiles of p-cymene (PC), a monocyclic monoterpene, and its possible mechanisms of action.
  
  
  METHODS
  Mice treated acutely with PC (25, 50, or 100 mg/kg, i.p.) were screened for carrageenan-induced hyperalgesia and the inflammatory components of its cascade (30-180 min), carrageenan-induced pleurisy (4 h), and tail-flick test (1-8 h). Also, we observed the PC effect on the generation of nitric oxide by macrophages and the activation of neurons in the periaqueductal gray (PAG) by immunofluorescence.
  
  
  RESULTS
  PC reduced (p < 0.001) the hyperalgesia induced by carrageenan, TNF-α, dopamine, and PGE2. PC decrease total leukocyte migration (100 mg/kg: p < 0.01), neutrophils (50 and 100 mg/kg: p < 0.05 and 0.001), and TNF-α (25, 50, and 100 mg/kg: p < 0.01, 0.05, and 0.001, respectively), besides reducing NO production (p < 0.05) in vitro. PC produced antinociceptive effect in tail-flick test (p < 0.05), which was antagonized by naloxone, naltrindole, nor-BNI, and CTOP, and increased (p < 0.001) the number of c-Fos-immunoreactive neurons in PAG.
  
  
  CONCLUSIONS
  These results provide information about the anti-hyperalgesic and anti-inflammatory properties of PC suggesting a possible involvement of the opioid system and modulating some pro-inflammatory cytokines.
authors: Department of Physiology and.
authors: Michele Fraga
authors: MF
authors: de Santana
authors: Adriana Gibara
authors: AG
authors: Guimarães
authors: Danielle Oliveira
authors: DO
authors: Chaves
authors: Juliane Cabral
authors: JC
authors: Silva
authors: Leonardo Rigoldi
authors: LR
authors: Bonjardim
authors: Waldecy
authors: W
authors: de Lucca Júnior
authors: Jamylle Nunes de Souza
authors: JN
authors: Ferro
authors: Emiliano de Oliveira
authors: Ede O
authors: Barreto
authors: Flávia Evangelista
authors: FE
authors: dos Santos
authors: Milena Botelho Pereira
authors: MB
authors: Soares
authors: Cristiane Flora
authors: CF
authors: Villarreal
authors: Jullyana de Souza Siqueira
authors: Jde S
authors: Quintans
authors: Lucindo José
authors: LJ
authors: Quintans-Júnior
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000081007:Cymenes; D016207:Cytokines / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D039821:Monoterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011957:Receptors, Opioid / Q000819:agonists / Q000502:physiology
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D000081007:Cymenes; D016207:Cytokines; D039821:Monoterpenes; D011957:Receptors, Opioid; C007210:4-cymene
keywords: Monoterpene; TNF-α; opioid system; pain