Most strategies to relieve neuropathic pain are aimed at the ion channels and neurotransmitters that govern overactive electrophysiological activity of neurons. But what if earlier stages of pain signaling could be targeted before nerve cells become hyperexcitable in the first place?
intracellular lipid signaling molecules with powerful analgesic effects might be key factors in this regard. Hammock and colleagues found that these molecules quelled neuropathic pain in rats by reducing endoplasmic reticulum (ER) stress, a state that arises when protein production within the cell falls out of balance, possibly leading to cell damage or death.
The work suggests that agents aimed at keeping ER stress in check might provide a new avenue to alleviate neuropathic pain.
ER stress— only very recently linked to pain at all
“We struggled for years to explain how increased levels of epoxides of arachidonic acid reduce symptoms of diabetes, block heart failure, and reduce inflammation, hypertension, and pain,” Hammock told PRF in an email. “It turns out that reducing ER stress is the common thread.
“The entire field of ER stress is relatively new—this area of research has accelerated in the last five years,”
“Pieces of the pathway have been studied for many years, and they have recently been unified by the general term ‘ER stress,’ ” Hammock told PRF. ER stress has been found to contribute to neurodegenerative diseases including Alzheimer’s disease and amyotrophic lateral sclerosis (ALS), but until recently, little was known about how it affects the peripheral nervous system.
Hammock had been investigating arachidonic acid-derived lipids called epoxy fatty acids (EFAs).
The great majority of analgesic drugs, including aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), target enzymes in the cascade, Hammock said. “But while aspirin and NSAIDs block the production of pro-inflammatory mediators, in our previous studies we were stabilizing natural anti-inflammatory molecules—the EFAs.”
Changing the conception and treatment of neuropathic pain
The results may have far-reaching implications for scientists’ understanding of neuropathic pain. Although skin biopsies from people with neuropathic pain show signs of nerve pathology, it has remained unknown what intracellular events govern the retraction of sensory nerve processes—one of the main indicators of neuropathy. Porreca said the findings “strongly support the idea that ER stress is an important mechanism that promotes pain and neuronal excitability,” but added that determining a causal role will require further investigation.
In the meantime, exactly how EFAs prevent ER stress, hyperexcitability, and pain remains unclear, but the group’s previous work suggests that the lipid signaling molecules work at least in part by affecting neurosteroids and GABAergic signaling (Inceoglu et al., 2013). “Every time a new mechanism is discovered, it opens up a bunch of new black boxes,” Hammock said.
The original discovery of the link between ER stress and neuropathic pain:
Researchers find key mechanism that causes neuropathic pain
ER stress is emerging as the cause of many health syndromes:
ER Stress and the Inflammatory Basis of Metabolic Disease
For more detail:
Endoplasmic reticulum stress: unfolded protein response (UPR)