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

IntroductionClinical 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.MethodsUnilateral 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.ResultsThe 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.ConclusionsTo 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.

99mTc-NTP 15-5 Imaging for Cartilage Involvement in Experimental Rheumatoid Arthritis: Comparison with Routinely Used Molecular Imaging Methods and Sensitivity to Chronic Nonsteroidal Antiinflammatory Drug Treatment

“…For RA induction, 12 mL of complete Freund adjuvant (0640; DIFCO Laboratories) containing heat-inactivated Mycobacterium butyricum (5 mg/mL) in paraffin oil were intraarticularly injected into the tibiotarsal joint of the right hind paw of CD1 male mice (Charles River) on day 0 (19,20). Shams received only the vehicle.…”

Involvement of GPR40, a long-chain free fatty acid receptor, in the production of central post-stroke pain after global cerebral ischemia

“…PUFAs are involved in many physiological functions, including brain and retinal development, aging, memory, synaptic membrane function, photoreceptor function, and neuroprotection (Bazan, 2003(Bazan, , 2006Eady et al, 2014;Hong et al, 2014). Recently, PUFAs such as DHA have been reported to interact with some pain conditions (Figueroa et al, 2013;Torres-Guzman et al, 2014). We recently reported that DHA and/or GW9508, a GPR40 agonist, have suppressive effects on pain behavior elicited by formalin, acetic acid and a complete Freund's adjuvant.…”

Implications for eicosapentaenoic acid- and docosahexaenoic acid-derived resolvins as therapeutics for arthritis

“…For instance, therapeutic chronic oral or intraarticular administration of DHA (10 mg/kg daily and 20 μg/knee) reduced pain-related behaviors and knee edema in arthritis induced by complete Freund's adjuvant (Torres-Guzman et al, 2014). In other work, using prophylactic DHA (1000 mg/kg and 25000 mg/kg daily for 4 weeks before induction of arthritis) treatment in complete Freund's adjuvant induced arthritis, proved to decrease clinical score and incidence.…”