Chronic, inflammatory, neuropathic, or incisional pain is affecting about 20 % of the adult population and up to 50 % of the elderly population. It thus represent a real public health issue. Despite the existence of large families of analgesics, treatments are often ineffective. This is due in large part to a lack of knowledge of the patho-physiological mechanisms of pain. During my PhD, I have been interested in the roles and regulation of molecular sensors of the pain recently highlighted: ion channels (ASICs "Acid Sensing Ion Channels "). ASICs constitute a family of excitatory cationic channels. The ASIC3 channels, in particular, are present in sensory neurons that innervate the skin, muscles, organs and joints. They are activated by low extracellular acidification occurring in many patho-physiological mechanisms such as inflammation, ischemia, tumor growth, or the subsequent tissue damage, for example, surgery. In a first study, we showed that ASIC3 channels play a crucial role in the development of post -operative pain, including postural pain, close to clinical cases. From a plantar incision model in rats, we demonstrated an over-expression of ASIC3 channels in sensory neurons innervating the operated hindpaw. Pharmacological inhibition (with toxin) and invalidation (siRNA) of ASIC3 in vivo reduce pain behavior. Our second study focused on the human ASIC3 channel, not yet extensively studied. I demonstrated that this channel has a unique and inducible property which gives it a sensitivity not only to acidification, but also to the extracellular alkalinization. This alkaline sensitivity is an intrinsic characteristic of the channel. It involves two specific arginine residues in the human channel that are present in its extracellular loop.Thus the human ASIC3 channel adapts its activity at different pH environments, and could participate in the fine regulation of membrane potential and neuronal sensitization. More recently, I have studied the regulation of ASIC3 channel by inflammatory lipids and there effects on pain. Interestingly, I showed that lysophosphatidylcholine (LPC), a lipid produced from the degradation of the membrane during inflammation, is a new activator of ASIC3 channel under normal pH conditions. Moreover, in synergy with moderate acidosis (pH 7.0), the LPC and its non-metabolizable analogue produce spontaneous pain in rats. This pain is reduced in the presence of the ASIC3 inhibitory toxin.
