Metabolomics uncovers dietary omega-3 fatty acid-derived metabolites implicated in anti-nociceptive responses after experimental spinal cord injury

Abstract

Chronic neuropathic pain is a frequent comorbidity following spinal cord injury (SCI) and often fails to respond to conventional pain management strategies. Preventive administration of docosahexaenoic acid (DHA) or consumption of a diet rich in omega-3 polyunsaturated fatty acids (O3PUFAs) confers potent prophylaxis against SCI and improves functional recovery. The present study examines whether this novel dietary strategy provides significant antinociceptive benefits in rats experiencing SCI-induced pain. Rats were fed control chow or chow enriched with O3PUFAs for 8 weeks before being subjected to sham or cord contusion surgeries, continuing the same diets after surgery for another 8 more weeks. The paw sensitivity to noxious heat was quantified for at least 8 weeks post-SCI using the Hargreaves test. We found that SCI rats consuming the preventive O3PUFA-enriched diet exhibited a significant reduction in thermal hyperalgesia compared to those consuming the normal diet. Functional neurometabolomic profiling revealed a distinctive deregulation in the metabolism of endocannabinoids (eCB) and related N-acyl ethanolamines (NAEs) at 8 weeks post-SCI. We found that O3PUFAs consumption led to a robust accumulation of novel NAE precursors, including the glycerophospho-containing docosahexaenoyl ethanolamine (DHEA), docosapentaenoyl ethanolamine (DPEA), and eicosapentaenoyl ethanolamine (EPEA). The tissue levels of these metabolites were significantly correlated with the antihyperalgesic phenotype. In addition, rats consuming the O3PUFA-rich diet showed reduced sprouting of nociceptive fibers containing CGRP and dorsal horn neuron p38 MAPK expression, well-established biomarkers of pain. The spinal cord levels of inositols were positively correlated with thermal hyperalgesia, supporting their role as biomarkers of chronic neuropathic pain. Notably, the O3PUFA-rich dietary intervention reduced the levels of these metabolites. Collectively, these results demonstrate the prophylactic value of dietary O3PUFA against SCI-mediated chronic pain.

Neuropathic ocular pain: an important yet underevaluated feature of dry eye

“…119,120 Furthermore, some current dry eye treatments, such as omega 3 and doxycycline (an MMP inhibitor), likely have a direct effect on nerve function along with secondary effects by improving the ocular surface environment. [121][122][123] Further studies are needed to assess whether topical and/or centrally acting neuromodulators have a role in the treatment of dry eye patients with features of NOP.…”

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.…”

The Mediterranean Diet as First Medicine

“…Concomitantly, it has been demonstrated that treatment of pain (it is calculated some 40-60% sufferers) in Alzheimer's patients (unable to report it) minimizes serious behavioral and psychological symptoms (agitation, aggression, etc) [15]. Incidentally, it has been reported that DHA reduces experimentally induced chronic pain [16].…”