The Prospect for Potent Sodium Voltage-Gated Channel Blockers to Relieve an Excessive Cough

An excessive, irritable, productive or non-productive coughing associated with airway inflammation belongs to pathological cough. Increased activation of airway vagal nociceptors in pathological conditions results from dysregulation of the neural pathway that controls cough. A variety of mediators associated with airway inflammation overstimulate these vagal airway fibers including C-fibers leading to hypersensitivity and hyperreactivity. Because current antitussives have limited efficacy and unwanted side effects there is a continual demand for the development of a novel more effective antitussives for a new efficacious and safe cough treatment. Therefore, inhibiting the activity of these vagal C-fibers represents a rational approach to the development of effective antitussive drugs. This may be achieved by blocking inflammatory mediator receptors or by blocking the generator potential associated with the specific ion channels. Because voltage-gated sodium channels (NaVs) are absolutely required for action potentials initiation and conduction irrespective of the stimulus, NaVs become a promising neural target. There is evidence that NaV1.7, 1.8 and 1.9 subtypes are predominantly expressed in airway cough-triggering nerves. The advantage of blocking these NaVs is suppressing C-fiber irrespective to stimuli, but the disadvantage is that by suppressing the nerves is may also block beneficial sensations and neuronal reflex behavior. The concept is that new antitussive drugs would have the benefit of targeting peripheral airway nociceptors without inhibiting the protective cough reflex.

Role of Dysregulated Ion Channels in Sensory Neurons in Chronic Kidney Disease-Associated Pruritus

Background: We investigated ion channels at the skin, including peripheral nerve endings, which serve as output machines and molecular integrators of many pruritic inputs mainly received by multiple G protein-coupled receptors (GPCRs). Methods: Based on the level of chronic kidney disease–associated pruritus (CKD-aP), subjects were divided into two groups: non-CKD-aP (no or slight pruritus; n = 12) and CKD-aP (mild, moderate, or severe pruritus; n = 11). Skin samples were obtained from the forearm or elbow during operations on arteriovenous fistulas. We measured ion channels expressed at the skin, including peripheral nerve endings by RT-PCR: Nav1.8, Kv1.4, Cav2.2, Cav3.2, BKCa, Anoctamin1, TRPV1, TRPA1, and ASIC. Results: Expression of Cav3.2, BKCa, and anoctamin1 was significantly elevated in patients with CKD-aP. On the other hand, expression of TRPV1 was significantly reduced in these patients. We observed no significant difference in the levels of Cav2.2 or ASIC between subjects with and without CKD-aP. TRPA1, Nav1.8, and Kv1.4 were not expressed. Conclusions: It was concluded that this greater difference in the expression of ion channels in the skin tissue including, specially cutaneous peripheral nerve endings in CKD patients with CKD-aP may increase generator potential related to itching.

Chronic Kidney Disease–Associated Pruritus is Caused by Dysregulated Ion Channels in Sensory Neurons

Background: We investigated ion channels at the skin, including peripheral nerve endings, which serve as output machines and molecular integrators of many pruritic inputs mainly received by multiple G protein-coupled receptors (GPCRs). Methods: Based on the level of chronic kidney disease–associated pruritus (CKD-aP), subjects were divided into two groups: non-CKD-aP (no or slight pruritus; n=12) and CKD-aP (mild, moderate, or severe pruritus; n=11). Skin samples were obtained from the forearm or elbow during operations on arteriovenous fistulas. We measured ion channels expressed at the skin, including peripheral nerve endings by RT-PCR: Nav1.8, Kv1.4, Cav2.2, Cav3.2, BKCa, Anoctamin1, TRPV1, TRPA1, and ASIC. Results: Expression of Cav3.2, BKCa, and anoctamin1 was significantly elevated in patients with CKD-aP. On the other hand, expression of TRPV1 was significantly reduced in these patients. We observed no significant difference in the levels of Cav2.2 or ASIC between subjects with and without CKD-aP. TRPA1, Nav1.8，and Kv1.4 were not expressed. Conclusions: It was concluded that this greater difference in expression of ion channels at the skin tissue including specific for cutaneous peripheral nerve endings in CKD patients with CKD-aP may increase generator potential related to itching.

Nucleobase-containing compounds evoke behavioural, olfactory, and transcriptional responses in model fishes

The sensory system of animals detects a massive and unknown array of chemical cues that evoke a diversity of physiological and behavioural responses. One group of nitrogen-containing carbon ring chemicals—nucleobases—are thought to be involved in numerous behaviours yet have received little attention. We took a top-down approach to examine responses evoked by nucleobases at behavioural, tissue, and gene expression levels. Fish generally avoided nucleobases, and this behaviour, when observed, was driven by purines but not pyrimidines. At the tissue level, olfactory neuron generator potential responses tended to be concentration specific and robust at concentrations lower than amino acid detection ranges. In terms of gene expression, more than 2000 genes were significantly upregulated following nucleobase exposure, some of which were expected (e.g., genes involved in purine binding) and some of which were not (e.g., tubulin-related genes). Humanized RNA pathway analysis showed that we had exposed the animal to a nucleobase. Our data indicate that responses to nucleobase-containing compounds may be highly structure based and are evident from changes in behaviour to mRNA expression. Many of these responses were surprising, and all provide numerous routes for further research endeavour.

Optogenetic activation of mechanically insensitive afferents in mouse colorectum reveals chemosensitivity

The sensory innervation of the distal colorectum includes mechanically insensitive afferents (MIAs; ∼25%), which acquire mechanosensitivity in persistent visceral hypersensitivity and thus generate de novo input to the central nervous system. We utilized an optogenetic approach to bypass the process of transduction (generator potential) and focus on transformation (spike initiation) at colorectal MIA sensory terminals, which is otherwise not possible in typical functional studies. From channelrhodopsin2-expressing mice (driven by Advillin-Cre), the distal colorectum with attached pelvic nerve was harvested for ex vivo single-fiber recordings. Afferent receptive fields (RFs) were identified by electrical stimulation and tested for response to mechanical stimuli (probing, stroking, and stretch), and afferents were classified as either MIAs or mechanosensitive afferents (MSAs). All MIA and MSA RFs were subsequently stimulated optically and MIAs were also tested for activation/sensitization with inflammatory soup (IS), acidic hypertonic solution (AHS), and/or bile salts (BS). Responses to pulsed optical stimuli (1–10 Hz) were comparable between MSAs and MIAs whereas 43% of MIAs compared with 86% of MSAs responded tonically to stepped optical stimuli. Tonic-spiking MIAs responded preferentially to AHS (an osmotic stimulus) whereas non-tonic-spiking MIAs responded to IS (an inflammatory stimulus). A significant proportion of MIAs were also sensitized by BS. These results reveal transformation as a critical factor underlying the differences between MIAs (osmosensors vs. inflammatory sensors), revealing a previously unappreciated heterogeneity of MIA endings. The current study draws attention to the sensory encoding of MIA nerve endings that likely contribute to afferent sensitization and thus have important roles in visceral pain.

Input–output mapping reconstruction of spike trains at dorsal horn evoked by manual acupuncture

In this study, a generalized linear model (GLM) is used to reconstruct mapping from acupuncture stimulation to spike trains driven by action potential data. The electrical signals are recorded in spinal dorsal horn after manual acupuncture (MA) manipulations with different frequencies being taken at the “Zusanli” point of experiment rats. Maximum-likelihood method is adopted to estimate the parameters of GLM and the quantified value of assumed model input. Through validating the accuracy of firings generated from the established GLM, it is found that the input–output mapping of spike trains evoked by acupuncture can be successfully reconstructed for different frequencies. Furthermore, via comparing the performance of several GLMs based on distinct inputs, it suggests that input with the form of half-sine with noise can well describe the generator potential induced by acupuncture mechanical action. Particularly, the comparison of reproducing the experiment spikes for five selected inputs is in accordance with the phenomenon found in Hudgkin–Huxley (H–H) model simulation, which indicates the mapping from half-sine with noise input to experiment spikes meets the real encoding scheme to some extent. These studies provide us a new insight into coding processes and information transfer of acupuncture.