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. Author manuscript; available in PMC: 2024 Aug 1.
Published in final edited form as: Pharmacol Ther. 2023 Jun 1;248:108454. doi: 10.1016/j.pharmthera.2023.108454

Figure 3. Mechanisms for regulatory lipids in pain signaling in neurons.

Figure 3.

The following four pathways are proposed mechanisms for how EpFA and vicinal diols activate and regulate pain: 1) 12,13-DiHOMEs directly activate TRPV1 receptors, increasing neurotransmission. EpFA activate BK channels (Yamaura, et al., 2006) and complex with TRP channels to hyperpolarize the neuron and downregulate neurotransmission; 2) In postsynaptic neurons, agonists of mu opioid receptors activate GIRK channels resulting in K+ release and hyperpolarization of the neuron. EpFA also activate GIRK channels in postsynaptic neurons and could help in understanding why preventing EpFA formation, either genetically or pharmaceutically, reduces morphine analgesia; 3) 11,12-DiHETrE blocks Kv1.2, downstream of opioid signaling, although the effects of increased diols on morphine efficacy have not been studied; and 4) 11,12-DiHETrE significantly blocks Kv4.2, an important potassium channel in pain relief.