Sensory neurons in the airways are finely tuned to respond to reactive chemicals threatening airway function and integrity. Nasal trigeminal nerve endings are particularly sensitive to oxidants formed in polluted air and during oxidative stress as well as to chlorine, which is frequently released in industrial and domestic accidents. Oxidant activation of airway neurons induces respiratory depression, nasal obstruction, sneezing, cough, and pain. While normally protective, chemosensory airway reflexes can provoke severe complications in patients affected by inflammatory airway conditions like rhinitis and asthma. Here, we showed that both hypochlorite, the oxidizing mediator of chlorine, and hydrogen peroxide, a reactive oxygen species, activated Ca 2+ influx and membrane currents in an oxidant-sensitive subpopulation of chemosensory neurons. These responses were absent in neurons from mice lacking TRPA1, an ion channel of the transient receptor potential (TRP) gene family. TRPA1 channels were strongly activated by hypochlorite and hydrogen peroxide in primary sensory neurons and heterologous cells. In tests of respiratory function, Trpa1 -/-mice displayed profound deficiencies in hypochlorite-and hydrogen peroxide-induced respiratory depression as well as decreased oxidant-induced pain behavior. Our results indicate that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiological responses in vitro and in vivo.

After ischemic stroke, partial recovery of function frequently occurs and may depend on the plasticity of axonal connections. Here, we examine whether blockade of the Nogo-NogoReceptor (NgR) pathway might enhance axonal sprouting and thereby recovery after focal brain infarction. Mutant mice lacking NgR or Nogo-AB recover complex motor function after stroke more completely than do control animals. After a stroke, greater numbers of axons emanating from the undamaged cortex cross the midline to innervate the contralateral red nucleus and the ipsilateral cervical spinal cord; this axonal plasticity is enhanced in ngr ؊/؊ or nogo-ab ؊/؊ mice. In rats with middle cerebral artery occlusion, both the recovery of motor skills and corticofugal axonal plasticity are promoted by intracerebroventricular administration of a function-blocking NgR fragment. Behavioral improvement occurs when therapy is initiated 1 week after arterial occlusion. Thus, delayed pharmacological blockade of the NgR promotes subacute stroke recovery by facilitating axonal plasticity.

The release of methyl isocyanate in Bhopal, India, caused the worst industrial accident in history. Exposures to industrial isocyanates induce lacrimation, pain, airway irritation, and edema. Similar responses are elicited by chemicals used as tear gases. Despite frequent exposures, the biological targets of isocyanates and tear gases in vivo have not been identified, precluding the development of effective countermeasures. We use Ca(2+) imaging and electrophysiology to show that the noxious effects of isocyanates and those of all major tear gas agents are caused by activation of Ca(2+) influx and membrane currents in mustard oil-sensitive sensory neurons. These responses are mediated by transient receptor potential ankyrin 1 (TRPA1), an ion channel serving as a detector for reactive chemicals. In mice, genetic ablation or pharmacological inhibition of TRPA1 dramatically reduces isocyanate- and tear gas-induced nocifensive behavior after both ocular and cutaneous exposures. We conclude that isocyanates and tear gas agents target the same neuronal receptor, TRPA1. Treatment with TRPA1 antagonists may prevent and alleviate chemical irritation of the eyes, skin, and airways and reduce the adverse health effects of exposures to a wide range of toxic noxious chemicals.

Paclitaxel (Taxol) is a well established chemotherapeutic agent for the treatment of solid tumors, but it is limited in its usefulness by the frequent induction of peripheral neuropathy. We found that prolonged exposure of a neuroblastoma cell line and primary rat dorsal root ganglia with therapeutic concentrations of Taxol leads to a reduction in inositol trisphosphate (InsP 3)-mediated Ca 2؉ signaling. We also observed a Taxol-specific reduction in neuronal calcium sensor 1 (NCS-1) protein levels, a known modulator of InsP 3 receptor (InsP3R) activity. This reduction was also found in peripheral neuronal tissue from Taxol treated animals. We further observed that short hairpin RNA-mediated NCS-1 knockdown had a similar effect on phosphoinositide-mediated Ca 2؉ signaling. When NCS-1 protein levels recovered, so did InsP 3-mediated Ca 2؉ signaling. Inhibition of the Ca 2؉ -activated protease -calpain prevented alterations in phosphoinositide-mediated Ca 2؉ signaling and NCS-1 protein levels. We also found that NCS-1 is readily degraded by -calpain in vitro and that -calpain activity is increased in Taxol but not vehicle-treated cells. From these results, we conclude that prolonged exposure to Taxol activates -calpain, which leads to the degradation of NCS-1, which, in turn, attenuates InsP 3-mediated Ca 2؉ signaling. These findings provide a previously undescribed approach to understanding and treating Taxolinduced peripheral neuropathy.calcium imaging ͉ dorsal root ganglia ͉ endoplasmic reticulum ͉ polyneuropathy ͉ inositol 1,4,5-trisphosphate receptor

Plants, fungi, and animals generate a diverse array of deterrent natural products that induce avoidance behavior in biological adversaries. The largest known chemical family of deterrents are terpenes characterized by reactive ␣,␤-unsaturated dialdehyde moieties, including the drimane sesquiterpenes and other terpene species. Deterrent sesquiterpenes are potent activators of mammalian peripheral chemosensory neurons, causing pain and neurogenic inflammation. Despite their widespread synthesis and medicinal use as desensitizing analgesics, their molecular targets remain unknown. Here we show that isovelleral, a noxious fungal sesquiterpene, excites sensory neurons through activation of TPRA1, an ion channel involved in inflammatory pain signaling. TRPA1 is also activated by polygodial, a drimane sesquiterpene synthesized by plants and animals. TRPA1-deficient mice show greatly reduced nocifensive behavior in response to isovelleral, indicating that TRPA1 is the major receptor for deterrent sesquiterpenes in vivo. Isovelleral and polygodial represent the first fungal and animal small molecule agonists of nociceptive transient receptor potential channels.Terpenes represent the largest group of natural products synthesized by plants, fungi, animals, and microorganisms (1). Although some terpenes function as hormonal messengers or as constituents of biological membranes and enzymatic cofactors, the biological functions of most of the ϳ25,000 different terpenes remain to be determined (1). Recent studies investigating the biochemical interactions of plants, fungi, and animals suggest that one of the major biological roles of terpenes is to act as chemical deterrents against herbivores, fungivores, and predators, respectively (1, 2). Deterrent terpenes interact with chemosensory detection systems in target organisms to induce avoidance behavior. In animals, it has been speculated that chemodefensive terpenes could activate gustatory and olfactory pathways as well as pain-sensing neuronal pathways. Indeed, some terpenes produce a painfully pungent taste in humans, probably related to their deterrent function.Recent research on terpene deterrents has focused on sesquiterpenes, a class of terpenes consisting of three isoprene units. One of the most intensively studied defensive sesquiterpenes is isovelleral, the pungent product of the fungus Lactarius vellereus. Isovelleral is thought to be part of a fungal chemical defense system against predators (3, 4) and is rapidly synthesized in response to injury from chemical precursors stored in the fungal laticiferous hyphae (5, 6). In behavioral tests, fungivorous mammals were strongly repelled by isovelleral (5, 6). In humans, skin contact with the fungal milky exudate often leads to painful inflammatory responses, including eczema and blistering (7,8). Another pungent sesquiterpene is polygodial, initially isolated from the leaves of water pepper (Polygonum hydropiper) (9). Polygodial is also a major product of winter's bark (Drimys winteri), a South American medicinal tree, ...