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Pain management remains a major challenge in medicine, highlighting the need for the development of new therapeutic agents. The transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are ion channels that play key roles in pain perception. Targeting both TRPA1 and TRPV1 simultaneously with dual antagonists offers a promising approach to pain relief. In this study, we investigated a series of hybrid analogs of TRPA1 and TRPV1 antagonists to discover novel therapeutic agents for pain. Among these compounds synthesized by a condensation reaction forming 1,2,4-oxadiazole between the A- and C-regions, compound 50 exhibited substantial dual-acting antagonism to TRPA1 and TRPV1 with IC50 values of 1.42, 2.84, 2.13, and 5.02 μM for hTRPA1, mTRPA1, hTRPV1, and rTRPV1, respectively. In the formalin test, compound 50 demonstrated dose-dependent analgesic activity with an ED50 of 85.9 mg/kg in phase 1 and 21.6 mg/kg in phase 2, respectively, and was able to inhibit pain behavior completely at a dose of 100 mg/kg. This study presents the discovery and characterization of a novel dual TRPA1/TRPV1 antagonist, highlighting its potential as a therapeutic agent for pain management.

Modulation of the function of somatosensory neurons is an important analgesic strategy, requiring the proposal of novel molecular targets. Many G-protein-coupled receptors (GPRs) have been deorphanized, but the receptor locations, outcomes due to their activations, and their signal transductions remain to be elucidated, regarding the somatosensory nociceptor function. Here we report that GPR171, expressed in a nociceptor subpopulation, attenuated pain signals via Gi/o-coupled modulation of the activities of nociceptive ion channels when activated by its newly found ligands. Administration of its natural peptide ligand and a synthetic chemical ligand alleviated nociceptor-mediated acute pain aggravations and also relieved pathologic pain at nanomolar and micromolar ranges. This study suggests that functional alteration of the nociceptor neurons by GPR171 signaling results in pain alleviation and indicates that GPR171 is a promising molecular target for peripheral pain modulation.

Peripheral nociceptors and their synaptic partners utilize neuropeptides for signal transmission. Such communication tunes the excitatory and inhibitory function of nociceptor-based circuits, eventually contributing to pain modulation. Corticotropin-releasing hormone (CRH) is the initiator hormone for the conventional hypothalamic-pituitary-adrenal axis, preparing our body for stress insults. Although knowledge of the expression and functional profiles of CRH and its receptors and the outcomes of their interactions has been actively accumulating for many brain regions, those for nociceptors are still under gradual investigation. Currently, based on the evidence of their expressions in nociceptors and their neighboring components, several hypotheses for possible pain modulations are emerging. Here we overview the historical attention to CRH and its receptors on the peripheral nociception and the recent increases in information regarding their roles in tuning pain signals. We also briefly contemplate the possibility that the stress-response paradigm can be locally intrapolated into intercellular communication that is driven by nociceptor neurons. Such endeavors may contribute to a more precise view of local peptidergic mechanisms of peripheral pain modulation.

Oxidative stress induces numerous biological problems. Lipid oxidation and peroxidation appear to be important steps by which exposure to oxidative stress leads the body to a disease state. For its protection, the body has evolved to respond to and eliminate peroxidation products through the acquisition of binding proteins, reducing and conjugating enzymes, and excretion systems. During the past decade, researchers have identified a group of ion channel molecules that are activated by oxidized lipids: transient receptor potential (TRP) channels expressed in sensory neurons. These ion channels are fundamentally detectors and signal converters for body-damaging environments such as heat and cold temperatures, mechanical attacks, and potentially toxic substances. When messages initiated by TRP activation arrive at the brain, we perceive pain, which results in our preparing defensive responses. Excessive activation of the sensory neuronal TRP channels upon prolonged stimulations sometimes deteriorates the inflammatory state of damaged tissues by promoting neuropeptide release from expresser neurons. These same paradigms may also work for pathologic changes in the internal lipid environment upon exposure to oxidative stress. Here, we provide an overview of the role of TRP channels and oxidized lipid connections during abnormally increased oxidative signaling, and consider the sensory mechanism of TRP detection as an alert system.

Lipids have long been studied as constituents of the cellular architecture and energy stores in the body. Evidence is now rapidly growing that particular lipid species are also important for molecular and cellular signaling. Here we review the current information on interactions between lipids and transient receptor potential (TRP) ion channels in nociceptive sensory afferents that mediate pain signaling. Sensory neuronal TRP channels play a crucial role in the detection of a variety of external and internal changes, particularly with damaging or pain-eliciting potentials that include noxiously high or low temperatures, stretching, and harmful substances. In addition, recent findings suggest that TRPs also contribute to altering synaptic plasticity that deteriorates chronic pain states. In both of these processes, specific lipids are often generated and have been found to strongly modulate TRP activities, resulting primarily in pain exacerbation. This review summarizes three standpoints viewing those lipid functions for TRP modulations as second messengers, intercellular transmitters, or bilayer building blocks. Based on these hypotheses, we discuss perspectives that account for how the TRP-lipid interaction contributes to the peripheral pain mechanism. Still a number of blurred aspects remain to be examined, which will be answered by future efforts and may help to better control pain states.