Epoxy fatty acids mediate analgesia in murine diabetic neuropathy

Abstract

Background Neuropathic pain is a debilitating condition with no adequate therapy. The health benefits of omega‐3 fatty acids are established, however, the role of docosahexaenoic acid (DHA) in limiting pain has only recently been described and the mechanisms of this action remain unknown. DHA is metabolized into epoxydocosapentanoic acids (EDPs) via cytochrome P450 (CYP450) enzymes which are substrates for the soluble epoxide hydrolase (sEH) enzyme. Here, we tested several hypotheses; first, that the antinociceptive action of DHA is mediated by the EDPs. Second, based on evidence that DHA and CYP450 metabolites elicit analgesia through opioid signalling, we investigated this as a possible mechanism of action. Third, we tested whether the analgesia mediated by epoxy fatty acids had similar rewarding effects as opioid analgesics. Methods We tested diabetic neuropathic wild‐type and sEH null mice in a conditioned place preference assay for their response to EDPs, sEHI and antagonism of these treatments with naloxone, a mu‐opioid receptor antagonist. Results The EDPs and sEH inhibitors were efficacious against chronic pain, and naloxone antagonized the action of both EDPs and sEH inhibitors. Despite this antagonism, the sEH inhibitors lacked reward side effects differing from opioids. Conclusions The EpFA are analgesic against chronic pain differing from opioids which have limited efficacy in chronic conditions. Significance EDPs and sEHI mediate analgesia in modelled chronic pain and this analgesia is blocked by naloxone. However, unlike opioids, sEHI are highly effective in neuropathic pain models and importantly lack rewarding side effects.

ω-3 Polyunsaturated fatty acids and their cytochrome P450-derived metabolites suppress colorectal tumor development in mice

“…Tumor sizing was measured using caliper, at the end of the experiment, the tumors were dissected, weighted and subjected to biochemical analysis. The EDPs are a synthetic mixture containing naturally occurring EDP regioisomers (7,8-, 10,11-, 13,14-, 16,17-, and 19,20-EDP), as we described [22]. …”

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

“…Studies employing this technique demonstrated the dose dependent efficacy of the sEHI, and importantly, that as potent analgesics, the sEHI lacked rewarding effects in the absence of pain (Wagner, et al, 2014). Importantly, direct administration of EpFA also induced a conditioned response in diabetic mice (Wagner, et al, 2016). Further investigation in a naturally occurring Type I diabetic mouse model (Akita) demonstrated the efficacy of the sEHI (Wagner, et al, 2017).…”

“…This work demonstrated inhibiting sEH did not produce reward seeking behavior (a conditioned place preference) in naïve and sEH null mice. Additionally, direct administration the EpFA demonstrated both analgesic efficacy against neuropathic pain as well as a lack of rewarding side effects (Wagner, et al, 2016). …”

Soluble epoxide hydrolase inhibition alleviates neuropathy in Akita (Ins2 Akita) mice

“…The EpFA are stabilized in vivo by the inhibition of the sEH and have demonstrated anti-inflammatory, antihypertensive, and analgesic properties [5–7]. The EpFA have also demonstrated efficacy against chemically induced diabetic neuropathy [8]. Here we use the Akita mouse model to inquire if sEH inhibition is analgesic in this naturally progressing disease, and importantly, if there are sexual dimorphisms in the pain responses.…”