Effects of cinnamaldehyde and related compounds on voltage-gated sodium and calcium channels

TRPA1 is a versatile sensory cation channel belonging to the Transient Receptor Potential (TRP) protein family. It plays a key role in the detection of numerous noxious chemicals and is involved in multiple inflammatory diseases. Most of the evidence on the pathophysiological role of TRPA1 has been gathered using the well-known irritant cinnamaldehyde (CA) under the assumption that it is a specific agonist of this channel. We have recently used this compound in several models of chemosensation, but surprisingly, we have found that CA only produces very weak responses, which is in sharp contrast with its powerful agonist action of CA on TRPA1. We thus hypothesize that this compound may inhibit the induction of excitatory neural activity (action potential firing) underlying pain sensation. In the present project we plan determine the molecular mechanisms underlying the TRPA1-independent effects of CA and related compounds in the somatosensory and cardiovascular systems. To achieve this we will employ wide variety of experimental and theoretical techniques (from fundamental channel biophysics and pharmacology to animal behavior) to address the following questions: What are the Na+ channel isoforms inhibited by CA? What are the molecular mechanisms underlying inhibition of voltage-gated Na+ channels? What are the effects of CA on intracellular Ca2+ dynamics and excitability of nociceptors? Is CA an analgesic or an anesthetic? Does CA modulate other excitatory channels such as voltage-gated Ca2+ channels? Do compounds structurally related to CA have similar analgesic/anesthetic properties? Our work will help to understand the mechanisms underlying novel and well-known pharmacological effects of CA, such as analgesia and the induction of blood pressure decrease. Moreover, this study will serve to explore the possibility of using CA, like capsaicin, as a desensitizer of nociceptors for the treatment of neuropathic pain, with the advantage of selective targeting neuronal populations without pain side effects.