Mechanisms of itch evoked by β-alanine.

β-Alanine, a popular supplement for muscle building, induces itch and tingling after consumption, but the underlying molecular and neural mechanisms are obscure. Here we show that, in mice, β-alanine elicited itch-associated behavior that requires MrgprD, a G-protein-coupled receptor expressed by a subpopulation of primary sensory neurons. These neurons exclusively innervate the skin, respond to β-alanine, heat, and mechanical noxious stimuli but do not respond to histamine.

In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans.

Native cowhage spicules, and heat-inactivated spicules containing histamine or capsaicin, evoke similar sensations of itch and nociceptive sensations in humans. In ongoing studies of the peripheral neural mechanisms of chemical itch and pain in the mouse, extracellular electrophysiological recordings were obtained, in vivo, from the cell bodies of mechanosensitive nociceptive neurons in response to spicule stimuli delivered to their cutaneous receptive fields (RFs) on the distal hindlimb. A total of 43 mechanosensitive, cutaneous, nociceptive neurons with axonal conduction velocities in the C-fiber range (C-nociceptors) were classified as CM if responsive to noxious mechanical stimuli, such as pinch, or CMH if responsive to noxious mechanical and heat stimuli (51°C, 5 s).

Mouse models of acute, chemical itch and pain in humans.

In psychophysical experiments, humans use different verbal responses to pruritic and algesic chemical stimuli to indicate the different qualities of sensation they feel. A major challenge for behavioural models in the mouse of chemical itch and pain in humans is to devise experimental protocols that provide the opportunity for the animal to exhibit a multiplicity of responses as well. One basic criterion is that chemicals that evoke primarily itch or pain in humans should elicit different types of responses when applied in the same way to the mouse.

Sensory responses to injection and punctate application of capsaicin and histamine to the skin.

A punctate, cutaneous application of capsaicin or histamine by means of a cowhage spicule elicits itch accompanied by pricking/stinging, burning, and typically, one or more areas of dysesthesia (alloknesis, hyperalgesia, hyperknesis). When applied over a wider and deeper area of skin by means of intradermal injection, histamine evokes the same sensory effects, but capsaicin evokes pain and hyperalgesia with allodynia instead of alloknesis. To examine the sensory effects of the spatial spread, depth, and amount of capsaicin and histamine, we applied different amounts of capsaicin or histamine by intradermal injection or by single vs multiple spicules within a circular cutaneous region of ~5 mm.

BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release.

Chronic itch accompanying many dermatological, neurological, and systemic diseases is unresponsive to antihistamines. Our knowledge of endogenous chemicals that evoke histamine-independent itch and their molecular targets is very limited. Recently it was demonstrated in behavioral and cellular experiments that bovine adrenal medulla 8-22 peptide (BAM8-22), a proteolytically cleaved product of proenkephalin A, is a potent activator of Mas-related G-protein-coupled receptors (Mrgprs), MrgprC11 and hMrgprX1, and induces scratching in mice in an Mrgpr-dependent manner.

Increased Na+ and K+ currents in small mouse dorsal root ganglion neurons after ganglion compression.

We investigated the effects of chronic compression (CCD) of the L3 and L4 dorsal root ganglion (DRG) on pain behavior in the mouse and on the electrophysiological properties of the small-diameter neuronal cell bodies in the intact ganglion. CCD is a model of human radicular pain produced by intraforaminal stenosis and other disorders affecting the DRG, spinal nerve, or root. On days 1, 3, 5, and 7 after the onset of compression, there was a significant decrease from preoperative values in the threshold mechanical force required to elicit a withdrawal of the foot ipsilateral to the CCD (tactile allodynia).

Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia.

Chronic pain is a major clinical problem and opiates are often the only treatment, but they cause significant problems ranging from sedation to deadly respiratory depression. Resiniferatoxin (RTX), a potent agonist of Transient Receptor Potential Vanilloid 1 (TRPV1), causes a slow, sustained and irreversible activation of TRPV1 and increases the frequency of spontaneous excitatory postsynaptic currents, but causes significant depression of evoked EPSCs due to nerve terminal depolarization block. Intrathecal administration of RTX to rats in the short-term inhibits nociceptive synaptic transmission, and in the long-term causes a localized, selective ablation of TRPV1-expressing central sensory nerve terminals leading to long lasting analgesia in behavioral models.

Similar itch and nociceptive sensations evoked by punctate cutaneous application of capsaicin, histamine and cowhage.

Itch evoked by cowhage or histamine is reduced or blocked by capsaicin desensitization, suggesting that pruriceptive neurons are capsaicin-sensitive. Topical capsaicin can evoke both nociceptive sensations and itch, whereas intradermal injection of capsaicin evokes only burning pain. To dissociate the pruritic and nociceptive sensory effects caused by the chemical activation of sensory neurons, chemicals were applied in a punctiform manner to the skin of the forearm using individual, heat-inactivated cowhage spicules treated with various concentrations of capsaicin (1-200 mg/ml) or histamine (0.

TRPV1: a target for next generation analgesics.

Transient Receptor Potential Vanilloid 1 (TRPV1) is a Ca(2+) permeant non-selective cation channel expressed in a subpopulation of primary afferent neurons. TRPV1 is activated by physical and chemical stimuli. It is critical for the detection of nociceptive and thermal inflammatory pain as revealed by the deletion of the TRPV1 gene.

Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse.

Sensory input from the periphery to the CNS is critically dependent on the strength of synaptic transmission at the first sensory synapse formed between primary afferent dorsal root ganglion (DRG) and superficial dorsal horn (DH) neurons of the spinal cord. Transient receptor potential vanilloid 1 (TRPV1) expressed on a subset of sensory neurons plays an important role in chronic inflammatory thermal nociception. Activation of protein kinase C (PKC) sensitizes TRPV1, which may contribute to the pathophysiology of chronic pain conditions.