title: Sildenafil enhances the peripheral antinociceptive effect of ellagic acid in the rat formalin test.
abstract: OBJECTIVE
  Ellagic acid (EA), a major polyphenolic compound of pomegranate juice, produces antinociceptive effects, which are mediated through opioidergic and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathways. The present study was conducted to elucidate the peripheral antinociceptive effect of EA alone and in combination with sildenafil in the rat formalin test.
  
  
  METHODS
  Pain was produced by intraplantar injection of formalin (2.5%) in rats and nociceptive behavior was measured as the number of flinches every 5 min in 60 min after injection.
  
  
  RESULTS
  Local administration of EA and sildenafil dose-dependently increased the nociception threshold in both phases of the test. Moreover, sub-effective doses of sildenafil (25 or 50 mcg/paw, i.p.) significantly and dose-dependently enhanced the antinociception induced by a sub-effective dose of EA (60 mcg/paw, i.pl.) in both phases of the test. The antinociception produced by these drugs alone, or in combination, was due to a peripheral site of action, since the administration in the contralateral paw was ineffective.
  
  
  CONCLUSIONS
  Our results suggest that EA has local peripheral antinociceptive activity, and enhancement of this effect with sildenafil probably occurs through the inhibition of cGMP metabolism.
authors.affiliation: Department of Pharmacology, School of Medicine, Physiology and Atherosclerosis Research Centers, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran ; Pain and Physiology Research Centers, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
authors.forename: Mohammad Taghi
authors.initials: MT
authors.lastname: Mansouri
authors.affiliation: Department of Pharmacology, School of Medicine, Physiology and Atherosclerosis Research Centers, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran ; Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Naghizadeh
authors.affiliation: Department of Pharmacology, School of Medicine, Physiology and Atherosclerosis Research Centers, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
authors.forename: Behnam
authors.initials: B
authors.lastname: Ghorbanzadeh
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004610:Ellagic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000700:Analgesics; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D004610:Ellagic Acid; D000068677:Sildenafil Citrate
keywords: Ellagic acid; formalin; peripheral antinociception; sildenafil
references.citation: Pain. 1996 Feb;64(2):345-355
references.pmid: 8740613
references.citation: Anticancer Res. 2001 Nov-Dec;21(6A):3903-8
references.pmid: 11911267
references.citation: J Ethnopharmacol. 2011 Jun 1;135(3):786-91
references.pmid: 21527327
references.citation: Pharmacol Biochem Behav. 2003 Aug;76(1):187-95
references.pmid: 13679232
references.citation: Pain. 1983 Jun;16(2):109-110
references.pmid: 6877845
references.citation: Pain. 1977 Dec;4(2):161-174
references.pmid: 564014
references.citation: J Nat Med. 2011 Jul;65(3-4):448-54
references.pmid: 21340514
references.citation: Cell Prolif. 2003 Dec;36(6):307-19
references.pmid: 14710849
references.citation: Br J Pharmacol. 2001 Sep;134(1):127-31
references.pmid: 11522604
references.citation: Br J Nutr. 2010 Apr;103(8):1102-9
references.pmid: 19948080
references.citation: Pharmacol Rev. 2006 Sep;58(3):488-520
references.pmid: 16968949
references.citation: Eur J Pharmacol. 2013 May 5;707(1-3):46-53
references.pmid: 23528359
references.citation: Eur J Pharmacol. 1990 Sep 21;186(2-3):289-93
references.pmid: 1981187
references.citation: Eur J Pain. 2002;6(1):25-34
references.pmid: 11888225
references.citation: J Perianesth Nurs. 2010 Aug;25(4):214-20
references.pmid: 20656257
references.citation: Prostaglandins. 1979 Aug;18(2):179-90
references.pmid: 230542
references.citation: Eur J Pharmacol. 2000 Jul 14;400(1):81-7
references.pmid: 10913588
references.citation: Pharmacol Biochem Behav. 2014 May;120:43-9
references.pmid: 24561064
references.citation: Br J Urol. 1996 Aug;78(2):257-61
references.pmid: 8813924
references.citation: J Pharm Pharmacol. 2006 Sep;58(9):1265-73
references.pmid: 16945186