A 'toothache tree' alkylamide inhibits Aδ mechanonociceptors to alleviate mechanical pain.

In traditional medicine, the 'toothache tree' and other plants of the Zanthoxylum genus have been used to treat inflammatory pain conditions, such as toothache and rheumatoid arthritis. Here we examined the cellular and molecular mechanisms underlying the analgesic properties of hydroxy-α-sanshool, the active alkylamide produced by Zanthoxylum plants. Consistent with its analgesic effects in humans, sanshool treatment in mice caused a selective attenuation of mechanical sensitivity under naïve and inflammatory conditions, with no effect on thermal sensitivity. To elucidate the molecular mechanisms by which sanshool attenuates mechanical pain, we performed single fibre recordings, calcium imaging and whole-cell electrophysiology of cultured sensory neurons. We found that: (1) sanshool potently inhibits Aδ mechanonociceptors that mediate both sharp acute pain and inflammatory pain; (2) sanshool inhibits action potential firing by blocking voltage-gated sodium currents in a subset of somatosensory neurons, which express a unique combination of voltage-gated sodium channels; and (3) heterologously expressed Nav1.7 is most strongly inhibited by sanshool as compared to other sodium channels expressed in sensory neurons. These results suggest that sanshool targets voltage-gated sodium channels on Aδ mechanosensory nociceptors to dampen excitability and thus induce 'fast pain' analgesia.

The star-nosed mole reveals clues to the molecular basis of mammalian touch.

Little is known about the molecular mechanisms underlying mammalian touch transduction. To identify novel candidate transducers, we examined the molecular and cellular basis of touch in one of the most sensitive tactile organs in the animal kingdom, the star of the star-nosed mole. Our findings demonstrate that the trigeminal ganglia innervating the star are enriched in tactile-sensitive neurons, resulting in a higher proportion of light touch fibers and lower proportion of nociceptors compared to the dorsal root ganglia innervating the rest of the body. We exploit this difference using transcriptome analysis of the star-nosed mole sensory ganglia to identify novel candidate mammalian touch and pain transducers. The most enriched candidates are also expressed in mouse somatosesensory ganglia, suggesting they may mediate transduction in diverse species and are not unique to moles. These findings highlight the utility of examining diverse and specialized species to address fundamental questions in mammalian biology.

TRPA1: A gatekeeper for inflammation.

Tissue damage evokes an inflammatory response that promotes the removal of harmful stimuli, tissue repair, and protective behaviors to prevent further damage and encourage healing. However, inflammation may outlive its usefulness and become chronic. Chronic inflammation can lead to a host of diseases, including asthma, itch, rheumatoid arthritis, and colitis. Primary afferent sensory neurons that innervate target organs release inflammatory neuropeptides in the local area of tissue damage to promote vascular leakage, the recruitment of immune cells, and hypersensitivity to mechanical and thermal stimuli. TRPA1 channels are required for neuronal excitation, the release of inflammatory neuropeptides, and subsequent pain hypersensitivity. TRPA1 is also activated by the release of inflammatory agents from nonneuronal cells in the area of tissue injury or disease. This dual function of TRPA1 as a detector and instigator of inflammatory agents makes TRPA1 a gatekeeper of chronic inflammatory disorders of the skin, airways, and gastrointestinal tract.

Behavioral choice between conflicting alternatives is regulated by a receptor guanylyl cyclase, GCY-28, and a receptor tyrosine kinase, SCD-2, in AIA interneurons of Caenorhabditis elegans.

Animals facing conflicting sensory cues make a behavioral choice between competing alternatives through integration of the sensory cues. Here, we performed a genetic screen to identify genes important for the sensory integration of two conflicting cues, the attractive odorant diacetyl and the aversive stimulus Cu(2+), and found that the membrane-bound guanylyl cyclase GCY-28 and the receptor tyrosine kinase SCD-2 regulate the behavioral choice between these alternatives in Caenorhabditis elegans. The gcy-28 mutants and scd-2 mutants show an abnormal bias in the behavioral choice between the cues, although their responses to each individual cue are similar to those in wild-type animals. Mutants in a gene encoding a cyclic nucleotide gated ion channel, cng-1, also exhibit the defect in sensory integration. Molecular genetic analyses suggested that GCY-28 and SCD-2 regulate sensory integration in AIA interneurons, where the conflicting sensory cues may converge. Genetic ablation or hyperpolarization of AIA interneurons showed nearly the same phenotype as gcy-28 or scd-2 mutants in the sensory integration, although this did not affect the sensory response to each individual cue. In gcy-28 or scd-2 mutants, activation of AIA interneurons is sufficient to restore normal sensory integration. These results suggest that the activity of AIA interneurons regulates the behavioral choice between the alternatives. We propose that GCY-28 and SCD-2 regulate sensory integration by modulating the activity of AIA interneurons.

Catecholamine receptor polymorphisms affect decision-making in C. elegans.

Innate behaviours are flexible: they change rapidly in response to transient environmental conditions, and are modified slowly by changes in the genome. A classical flexible behaviour is the exploration-exploitation decision, which describes the time at which foraging animals choose to abandon a depleting food supply. We have used quantitative genetic analysis to examine the decision to leave a food patch in Caenorhabditis elegans. Here we show that patch-leaving is a multigenic trait regulated in part by naturally occurring non-coding polymorphisms in tyra-3 (tyramine receptor 3), which encodes a G-protein-coupled catecholamine receptor related to vertebrate adrenergic receptors. tyra-3 acts in sensory neurons that detect environmental cues, suggesting that the internal catecholamines detected by tyra-3 regulate responses to external conditions. These results indicate that genetic variation and environmental cues converge on common circuits to regulate behaviour, and suggest that catecholamines have an ancient role in regulating behavioural decisions.

Physiological basis of tingling paresthesia evoked by hydroxy-alpha-sanshool.

Hydroxy-alpha-sanshool, the active ingredient in plants of the prickly ash plant family, induces robust tingling paresthesia by activating a subset of somatosensory neurons. However, the subtypes and physiological function of sanshool-sensitive neurons remain unknown. Here we use the ex vivo skin-nerve preparation to examine the pattern and intensity with which the sensory terminals of cutaneous neurons respond to hydroxy-alpha-sanshool. We found that sanshool excites virtually all D-hair afferents, a distinct subset of ultrasensitive light-touch receptors in the skin and targets novel populations of Abeta and C fiber nerve afferents. Thus, sanshool provides a novel pharmacological tool for discriminating functional subtypes of cutaneous mechanoreceptors. The identification of sanshool-sensitive fibers represents an essential first step in identifying the cellular and molecular mechanisms underlying tingling paresthesia that accompanies peripheral neuropathy and injury.

Mammalian somatosensory mechanotransduction.

In the mammalian somatosensory system, mechanosensitive neurons mediate the senses of touch and pain. Among sensory modalities, mechanosensation has been the most elusive with regard to the identification of transduction molecules. One factor that has hindered the identification of transduction molecules is the diversity of neurons; physiological studies have revealed many subtypes of neurons, specialized to detect a variety of mechanical stimuli. Do different subtypes use the same transduction molecules that are modified by cellular context? Or, are there multiple mechanotransducers that specialize in sensing different mechanical stimuli? This review highlights recent progress in identifying and characterizing candidate molecular force transducers, as well as the development of new tools to characterize touch transduction at the molecular, cellular, and behavioral levels.

A behavioral switch: cGMP and PKC signaling in olfactory neurons reverses odor preference in C. elegans.

Innate chemosensory preferences are often encoded by sensory neurons that are specialized for attractive or avoidance behaviors. Here, we show that one olfactory neuron in Caenorhabditis elegans, AWC(ON), has the potential to direct both attraction and repulsion. Attraction, the typical AWC(ON) behavior, requires a receptor-like guanylate cyclase GCY-28 that acts in adults and localizes to AWC(ON) axons. gcy-28 mutants avoid AWC(ON)-sensed odors; they have normal odor-evoked calcium responses in AWC(ON) but reversed turning biases in odor gradients. In addition to gcy-28, a diacylglycerol/protein kinase C pathway that regulates neurotransmission switches AWC(ON) odor preferences. A behavioral switch in AWC(ON) may be part of normal olfactory plasticity, as odor conditioning can induce odor avoidance in wild-type animals. Genetic interactions, acute rescue, and calcium imaging suggest that the behavioral reversal results from presynaptic changes in AWC(ON). These results suggest that alternative modes of neurotransmission can couple one sensory neuron to opposite behavioral outputs.

Dissecting a circuit for olfactory behaviour in Caenorhabditis elegans.

Although many properties of the nervous system are shared among animals and systems, it is not known whether different neuronal circuits use common strategies to guide behaviour. Here we characterize information processing by Caenorhabditis elegans olfactory neurons (AWC) and interneurons (AIB and AIY) that control food- and odour-evoked behaviours. Using calcium imaging and mutations that affect specific neuronal connections, we show that AWC neurons are activated by odour removal and activate the AIB interneurons through AMPA-type glutamate receptors. The level of calcium in AIB interneurons is elevated for several minutes after odour removal, a neuronal correlate to the prolonged behavioural response to odour withdrawal. The AWC neuron inhibits AIY interneurons through glutamate-gated chloride channels; odour presentation relieves this inhibition and results in activation of AIY interneurons. The opposite regulation of AIY and AIB interneurons generates a coordinated behavioural response. Information processing by this circuit resembles information flow from vertebrate photoreceptors to 'OFF' bipolar and 'ON' bipolar neurons, indicating a conserved or convergent strategy for sensory information processing.

APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos.

Early embryonic cells in Caenorhabditis elegans embryos interact through a signaling pathway closely related to the Notch signaling pathway in Drosophila and vertebrates. Components of this pathway include a ligand, receptor, the presenilin proteins, and a novel protein, APH-2, that is related to the Nicastrin protein in humans. Here we identify the aph-1 gene as a new component of the Notch pathway in Caenorhabditis elegans. aph-1 is predicted to encode a novel, highly conserved multipass membrane protein. We show that aph-1 and the presenilin genes share a similar function in that they are both required for proper cell-surface localization of APH-2/Nicastrin.