title: Chronic oral or intraarticular administration of docosahexaenoic acid reduces nociception and knee edema and improves functional outcomes in a mouse model of Complete Freund's Adjuvant-induced knee arthritis.
abstract: BACKGROUND
  Clinical and preclinical studies have shown that supplementation with ω-3 polyunsaturated fatty acids (ω-3 PUFAs) reduce joint destruction and inflammation present in rheumatoid arthritis (RA). However, the effects of individual ω-3 PUFAs on chronic arthritic pain have not been evaluated to date. Thus, our aim in this study was to examine whether purified docosahexaenoic acid (DHA, an ω-3 PUFA) reduces spontaneous pain-related behavior and knee edema and improves functional outcomes in a mouse model of knee arthritis.
  
  
  METHODS
  Unilateral arthritis was induced by multiple injections of Complete Freund's Adjuvant (CFA) into the right knee joints of male ICR adult mice. Mice that received CFA injections were then chronically treated from day 15 until day 25 post-initial CFA injection with oral DHA (10, 30 and 100 mg/kg daily) or intraarticular DHA (25 and 50 μg/joint twice weekly). Spontaneous flinching of the injected extremity (considered as spontaneous pain-related behavior), vertical rearing and horizontal exploratory activity (considered as functional outcomes) and knee edema were assessed. To determine whether an endogenous opioid mechanism was involved in the therapeutic effect of DHA, naloxone (NLX, an opioid receptor antagonist, 3 mg/kg subcutaneously) was administered in arthritic mice chronically treated with DHA (30 mg/kg by mouth) at day 25 post-CFA injection.
  
  
  RESULTS
  The intraarticular CFA injections resulted in increasing spontaneous flinching and knee edema of the ipsilateral extremity as well as worsening functional outcomes as time progressed. Chronic administration of DHA, given either orally or intraarticularly, significantly improved horizontal exploratory activity and reduced flinching behavior and knee edema in a dose-dependent manner. Administration of NLX did not reverse the antinociceptive effect of DHA.
  
  
  CONCLUSIONS
  To the best of our knowledge, this report is the first to demonstrate DHA's antinociceptive and anti-inflammatory effects as individual ω-3 PUFAs following sustained systemic and intraarticular administration in a mouse model of CFA-induced knee arthritis. The results suggest that DHA treatment may offer a new therapeutic approach to alleviate inflammation as well as a beneficial effect on pain-related functional disabilities in RA patients.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Torres-Guzman
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Morado-Urbina
authors.forename: Perla A
authors.initials: PA
authors.lastname: Alvarado-Vazquez
authors.forename: Rosa I
authors.initials: RI
authors.lastname: Acosta-Gonzalez
authors.forename: Aracely E
authors.initials: AE
authors.lastname: Chávez-Piña
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Montiel-Ruiz
authors.forename: Juan M
authors.initials: JM
authors.lastname: Jimenez-Andrade
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004487:Edema; D005620:Freund's Adjuvant / Q000633:toxicity; D007719:Knee Joint / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010146:Pain / Q000188:drug therapy* / Q000209:etiology
chemical_list: D004281:Docosahexaenoic Acids; D005620:Freund's Adjuvant