Natural Products and some semi-synthetic analogues as potential TRPV1 Ligands for attenuating Neuropathic pain

: Natural products and leads inspired by them have acted as a probe for successful drug discovery for many decades. Pain is an obnoxious sensory and emotional experience associated with potential tissue damage. It affects the quality of life of patients to a great extent. Despite the availability of several agents targeting TRP receptors, none of them can proficiently alleviate neuropathic pain. TRPV1 is a prospective target for treating neuropathic pain as it is recognized to modulate the pain circuitry at the periphery and central level. In this review, we have discussed several natural molecules (such as Capsaicinoids, capsinoids, Piperine, Eugenol, Scutigeral, Ginsenosides, Cinnamaldehyde, Camphor, Shogaol, Gingerols, Zingerone, Allicin, Evodiamine, Allylisothiocyanate, Cannabidiol, Ricinoleic acid, Isovelleral, Capsazepine, Thapsigargin, Pellitorine, Yohimbine, Curcumin) and some semi-synthetic analogues that activate TRPV1 channels, and can be further harnessed consequently for the treatment of neuropathic pain.

Effect of Capsaicin and Other Thermo-TRP Agonists on Thermoregulatory Processes in the American Cockroach

Capsaicin is known to activate heat receptor TRPV1 and induce changes in thermoregulatory processes of mammals. However, the mechanism by which capsaicin induces thermoregulatory responses in invertebrates is unknown. Insect thermoreceptors belong to the TRP receptors family, and are known to be activated not only by temperature, but also by other stimuli. In the following study, we evaluated the effects of different ligands that have been shown to activate (allyl isothiocyanate) or inhibit (camphor) heat receptors, as well as, activate (camphor) or inhibit (menthol and thymol) cold receptors in insects. Moreover, we decided to determine the effect of agonist (capsaicin) and antagonist (capsazepine) of mammalian heat receptor on the American cockroach’s thermoregulatory processes. We observed that capsaicin induced the decrease of the head temperature of immobilized cockroaches. Moreover, the examined ligands induced preference for colder environments, when insects were allowed to choose the ambient temperature. Camphor exposure resulted in a preference for warm environments, but the changes in body temperature were not observed. The results suggest that capsaicin acts on the heat receptor in cockroaches and that TRP receptors are involved in cockroaches’ thermosensation.

TRP Receptors in Arthritis, Gaining Knowledge for Translation from Experimental Models

Arthritis is a condition characterised by mainly pain, reduced joint movement and signs of inflammation, such as swelling. The disorder has many different types, of which osteoarthritis (a degenerative joint disease) and rheumatoid arthritis (a chronic autoimmune disease) are the two most common forms. There are >6 million sufferers in the UK and both conditions have a huge potential to impair capabilities and contribute to social and economic burdens. Whilst there are a wide range of arthritic therapies available, many patients under treatment complain of poor pain relief. Thus there is a need for novel therapeutic approaches, and the transient receptor potential (TRP) family of receptor channels has been investigated. One particular area of recent research has been the ligand-gated transient receptor potential vanilloid 1 (TRPV1) channel. Findings from numerous pre-clinical models and scientific studies have shown that TRPV1 desensitisation, or the use of TRPV1 antagonists alleviates pain and some inflammatory aspects. New findings have started to unveil the potential of other TRP channels in mediating arthritic pain and inflammation. With the understanding that the currently available treatments for arthritis are limited, researchers have looked into the exciting prospect that TRP receptor antagonists may be developed into effective, specific drugs, which would potentially protect against the complications of arthritis. These antagonists are still under development, although only data from studies from pre-clinical models are currently available. This review acts to summarize knowledge of the potential influence of TRP receptors in arthritis to date.

The menthol and cold sensation receptor TRPM8 in normal human nasal mucosa and rhinitis

Background: Menthol and cold sensation trigger symptoms and reflex responses in the upper airway, but the underlying molecular mechanisms are unknown. We have therefore studied nerve fibres expressing the menthol and cold receptor TRPM8 in normal human mucosa, and in rhinitis. TRPM8 nerve fibres were compared with those expressing other TRP receptors including TRPV1 (capsaicin and heat receptor), and TRPA1 (mechano-cold receptor). Methods: Immunohistology and image-analysis were used to study TRP receptors in biopsies of nasal turbinate from control subjects, patients with allergic rhinitis, and non-allergic rhinitis. Results: TRPM8-immunoreactive nerve fibres were observed in the sub-epithelium, and were profuse around blood vessels in deeper regions, where they were markedly greater in number than TRPV1+ fibers. Image analysis of TRPM8 in sub-epithelial and vascular regions showed no significant differences between control and the rhinitis patient groups. TRPA1-immunoreactivity was weak and seen rarely in nerve fibres. Conclusion: We show that TRPM8 nerve fibres are abundant in nasal mucosa particularly around blood vessels, and may mediate neurovascular reflexes. TRPM8 antagonists deserve consideration for therapeutic trial in rhinitis.