Neuropathic-like Nociception and Spinal Cord Neuroinflammation Are Dependent on the TRPA1 Channel in Multiple Sclerosis Models in Mice.

Background: Transient receptor potential ankyrin 1 (TRPA1) activation is implicated in neuropathic pain-like symptoms. However, whether TRPA1 is solely implicated in pain-signaling or contributes to neuroinflammation in multiple sclerosis (MS) is unknown. Here, we evaluated the TRPA1 role in neuroinflammation underlying pain-like symptoms using two different models of MS. Methods: Using a myelin antigen, Trpa1+/+ or Trpa1-/- female mice developed relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) (Quil A as adjuvant) or progressive experimental autoimmune encephalomyelitis (PMS)-EAE (complete Freund's adjuvant). The locomotor performance, clinical scores, mechanical/cold allodynia, and neuroinflammatory MS markers were evaluated. Results: Mechanical and cold allodynia detected in RR-EAE, or PMS-EAE Trpa1+/+ mice, were not observed in Trpa1-/- mice. The increased number of cells labeled for ionized calcium-binding adapter molecule 1 (Iba1) or glial fibrillary acidic protein (GFAP), two neuroinflammatory markers in the spinal cord observed in both RR-EAE or PMS-EAE Trpa1+/+ mice, was reduced in Trpa1-/- mice. By Olig2 marker and luxol fast blue staining, prevention of the demyelinating process in Trpa1-/- induced mice was also detected. Conclusions: Present results indicate that the proalgesic role of TRPA1 in EAE mouse models is primarily mediated by its ability to promote spinal neuroinflammation and further strengthen the channel inhibition to treat neuropathic pain in MS.

miRNA-203b-3p Induces Acute and Chronic Pruritus through 5-HTR2B and TRPV4.

Growing evidence indicates that transient receptor potential (TRP) channels contribute to different forms of pruritus. However, the endogenous mediators that cause itch through transient receptor potential channels signaling are poorly understood. In this study, we show that genetic deletion or pharmacological antagonism of TRPV4 attenuated itch in a mouse model of psoriasis induced by topical application of imiquimod. Human psoriatic lesions showed increased expression of several microRNAs, including the miR-203b-3p, which induced a calcium ion response in rodent dorsal root ganglion neurons and scratching behavior in mice through 5-HTR2B activation and the protein kinase C‒dependent phosphorylation of TRPV4. Computer simulation revealed that the miR-203b-3p core sequence (GUUAAGAA) that causes 5-HTR2B/TRPV4-dependent itch targets the extracellular side of 5-HTR2B by interacting with a portion of the receptor pocket consistent with its activation. Overall, we reveal the unconventional pathophysiological role of an extracellular microRNA that can behave as an itch promoter through 5-HTR2B and TRPV4.

Retinal Toxicity Induced by Chemical Agents.

Vision is an important sense for humans, and visual impairment/blindness has a huge impact in daily life. The retina is a nervous tissue that is essential for visual processing since it possesses light sensors (photoreceptors) and performs a pre-processing of visual information. Thus, retinal cell dysfunction or degeneration affects visual ability and several general aspects of the day-to-day of a person's lives. The retina has a blood-retinal barrier, which protects the tissue from a wide range of molecules or microorganisms. However, several agents, coming from systemic pathways, reach the retina and influence its function and survival. Pesticides are still used worldwide for agriculture, contaminating food with substances that could reach the retina. Natural products have also been used for therapeutic purposes and are another group of substances that can get to the retina. Finally, a wide number of medicines administered for different diseases can also affect the retina. The present review aimed to gather recent information about the hazard of these products to the retina, which could be used to encourage the search for more healthy, suitable, or less risky agents.

The anti-migraine component of butterbur extracts, isopetasin, desensitizes peptidergic nociceptors by acting on TRPA1 cation channel.

BACKGROUND AND PURPOSE: The mechanism of the anti-migraine action of extracts of butterbur [Petasites hybridus (L.) Gaertn.] is unknown. Here, we investigated the ability of isopetasin, a major constituent of these extracts, to specifically target TRPA1 channel and to affect functional responses relevant to migraine. EXPERIMENTAL APPROACH: Single-cell calcium imaging and patch-clamp recordings in human and rodent TRPA1-expressing cells, neurogenic motor responses in rodent isolated urinary bladder, release of CGRP from mouse spinal cord in vitro and facial rubbing in mice and meningeal blood flow in rats were examined. KEY RESULTS: Isopetasin induced (i) calcium responses and currents in rat/mouse trigeminal ganglion (TG) neurons and in cells expressing the human TRPA1, (ii) substance P-mediated contractions of rat isolated urinary bladders and (iii) CGRP release from mouse dorsal spinal cord, responses that were selectively abolished by genetic deletion or pharmacological antagonism of TRPA1 channels. Pre-exposure to isopetasin produced marked desensitization of allyl isothiocyanate (AITC, TRPA1 channel agonist)- or capsaicin (TRPV1 channel agonist)-evoked currents in rat TG neurons, contractions of rat or mouse bladder and CGRP release from mouse central terminals of primary sensory neurons. Repeated intragastric administration of isopetasin attenuated mouse facial rubbing, evoked by local AITC or capsaicin, and dilation of rat meningeal arteries by acrolein or ethanol (TRPA1 and TRPV1 channel agonists respectively). CONCLUSION AND IMPLICATIONS: Activation of TRPA1 channels by isopetasin results in excitation of neuropeptide-containing nociceptors, followed by marked heterologous neuronal desensitization. Such atten uation in pain and neurogenic inflammation may account for the anti-migraine action of butterbur.