Mouse Model of Touch-Evoked Itch (Alloknesis).
(2012)
Journal - The Journal of investigative dermatology
Abstract :
Lightly touching normal skin near a site of itch can elicit itch sensation, a phenomenon known as alloknesis. To investigate the neural mechanisms of alloknesis, we have developed an animal model. Low-threshold mechanical stimulation of the skin normally does not elicit any response in naive C57/BL6 mice. Following acute intradermal (i.d.) injection of histamine in the rostral back, mechanical stimulation 7?mm from the injection site elicited discrete hindlimb scratch bouts directed toward the stimulus. This began at 10?minutes and peaked 20-40?minutes post histamine injection, declining over the next hour. Histamine itself elicited bouts of scratching not associated with the mechanical stimulus, which ceased after 30?minutes. Histamine- and touch-evoked scratching was inhibited by the µ-opiate antagonist naltrexone. Touch-evoked scratching was observed following i.d. 5-HT (5-hydroxytryptamine), a protease-activated receptor (PAR)-4 agonist, and an MrgprC11 agonist BAM8-22, but not chloroquine or a PAR-2 agonist. The histamine H1 receptor antagonist terfenadine prevented scratching and alloknesis evoked by histamine, but not 5-HT, a PAR-4 agonist or an MrgprC11 agonist. In mice with experimental dry skin, there was a time-dependent increase in spontaneous and touch-evoked scratching. This animal model, appears to be useful to investigate neural mechanisms of itch and alloknesis.Journal of Investigative Dermatology advance online publication, 15 March 2012; doi:10.1038/jid.2012.52.
Enhanced responses of lumbar superficial dorsal horn neurons to intradermal PAR-2 agonist but not histamine in a mouse hindpaw dry skin itch model.
(2011)
Journal - Journal of neurophysiology (United States )
Abstract :
Chronic itch is symptomatic of many skin conditions and systemic diseases. Little is known about pathophysiological alterations in itch-signaling neural pathways associated with chronic itch. We used a mouse model of hindpaw chronic dry skin itch to investigate properties of presumptive itch-signaling neurons. Neurons in the lumbar superficial dorsal horn ipsilateral to hindpaw dry skin treatment exhibited a high level of spontaneous activity that was inhibited by scratching the plantar surface. Most spontaneously active units exhibited further increases in firing rate following intradermal injection of an agonist of the protease-activated receptor PAR-2, or histamine. The large majority of pruritogen-responsive units also responded to capsaicin and allyl isothiocyanate. For neurons ipsilateral to dry skin treatment, responses elicited by the PAR-2 agonist, but not histamine or mechanical stimuli, were significantly larger compared with neurons ipsilateral to vehicle (water) treatment or neurons recorded in naïve (untreated) mice. The spontaneous activity may signal ongoing itch, while enhanced PAR-2 agonist-evoked responses may underlie hyperknesis (enhanced itch), both of which are symptomatic of many chronic itch conditions. The enhancement of neuronal responses evoked by the PAR-2 agonist, but not by histamine or mechanical stimuli, implies that the dry skin condition selectively sensitized PAR-2 agonist-sensitive primary afferent pruriceptors.
Differential itch- and pain-related behavioral responses and µ-opoid modulation in mice.
(2010)
Journal - Acta dermato-venereologica (Sweden )
Abstract :
Intradermal microinjection of the pruritogen histamine, or the algogen capsaicin, in the mouse cheek differentially elicits mainly hindlimb scratching or ipsilateral forelimb wiping, respectively. We investigated the dose-dependency of these responses elicited by various pruritogens and algogens, and µ-opioid modulation. Histamine, 5-hydro-xytryptamine (5-HT) and agonists of protease-activated receptors PAR-2 and PAR-4, all elicited dose-related hindlimb scratching bouts with little forelimb wiping. In contrast, capsaicin, allyl isothiocyanate and bradykinin elicited dose-related forelimb wiping with little scratching. Morphine reduced capsaicin-evoked wiping but not pruritogen-evoked scratching. The µ-antagonist naltrexone decreased pruritogen-evoked scratching but not capsaicin-evoked wiping. A cowhage spicule inserted intradermal elicited equivalent scratching and wiping, while inactivated cowhage spicules loaded with histamine or capsaicin elicited significantly more scratching or wiping, respectively. The mouse cheek injection model appears to be a useful behavioral test that distinguishes between itch and pain.
Scratching behavior and Fos expression in superficial dorsal horn elicited by protease-activated receptor agonists and other itch mediators in mice.
(2009)
Journal - The Journal of pharmacology and experimental therapeutics (United States )
Abstract :
Protease-activated receptor (PAR)-2 and PAR-4 are implicated in nonhistaminergic itch. We investigated dose dependence, tachyphylaxis, and cross-tachyphylaxis of itch-associated scratching elicited by intradermal injections of PAR-2 and PAR-4 agonists, serotonin (5-hydroxytryptamine, 5-HT), and histamine in ICR mice, as well as mu-opioid modulation of PAR-2 agonist-evoked scratching. Each agent elicited dose-related increases in scratch bouts. Scratching elicited by the PAR-4 agonist and histamine both exhibited significant tachyphylaxis but no cross-tachyphylaxis with each other. Scratching evoked by 5-HT did not exhibit significant tachyphylaxis but did exhibit significant cross-tachyphylaxis to scratching evoked by the PAR-2 and PAR-4 agonists and histamine. Naltrexone and high-dose morphine (10 mg/kg) attenuated PAR-2 agonist-evoked scratching, whereas lower dose morphine (1 mg/kg) had no effect. High-dose morphine also significantly increased circling behavior, which may have interfered with scratching. The PAR-2 agonist and 5-HT produced overlapping distributions of Fos-like immunoreactivity in the superficial dorsal horn. These results indicate that PAR-2 and PAR-4 agonists, histamine, and 5-HT elicit itch-related scratching and activate superficial dorsal horn neurons that may participate in scratch reflex and ascending itch signaling pathways.
| ISSN : | 1521-0103 |
|---|
| Mesh Heading : | Animals Behavior, Animal Capsaicin Histamine Injections, Intradermal Mice Morphine Naltrexone Oligopeptides Posterior Horn Cells Proto-Oncogene Proteins c-fos Pruritus Receptor, PAR-2 Receptors, Opioid, mu Receptors, Proteinase-Activated Serotonin Spinal Cord Tachyphylaxis pharmacology pharmacology pharmacology analogs & derivatives pharmacology pharmacology drug effects agonists agonists pharmacology drug effects physiology |
|---|
| Mesh Heading Relevant : | drug effects metabolism metabolism chemically induced agonists metabolism |
|---|
Activation of superficial dorsal horn neurons in the mouse by a PAR-2 agonist and 5-HT: potential role in itch.
(2009)
Journal - The Journal of neuroscience : the official journal of the Society for Neuroscience (United States )
Abstract :
Itch, an unpleasant sensation associated with the desire to scratch, is symptomatic of dermatologic and systemic disorders that often resist antihistamine treatment. Histamine-independent itch mediators include serotonin (5-HT) and agonists of the protease-activated receptor-2 (PAR-2). We used behavior, Fos immunohistochemistry, and electrophysiology to investigate if these mediators activate spinal dorsal horn neurons in a manner consistent with itch. Intradermal (i.d.) injection of the PAR-2 agonist SLIGRL-NH(2) in the rostral back evoked bouts of directed hindlimb scratches over 20-30 min. Hindpaw injection of SLIGRL-NH(2) produced Fos staining in superficial dorsal horn which was then targeted for single-unit recording. Small id microinjections of SLIGRL-NH(2) or 5-HT identified responsive single units in the superficial dorsal horn of mice anesthetized with pentobarbital. Thirty-eight units characterized as wide dynamic range, nociceptive specific, or mechanically insensitive exhibited significantly increased firing after i.d. SLIGRL-NH(2) for 9 min, to partial (25%) tachyphylaxis with repeated injection. A majority additionally responded to 5-HT (70%), mustard oil (79%), and capsaicin (71%). Seven units isolated with the 5-HT search stimulus exhibited significant and prolonged responses to 5-HT with tachyphylaxis to repeated injections. The majority also responded to SLIGRL-NH(2), mustard oil, and capsaicin. The prolonged responses of superficial dorsal horn neurons to SLIGRL-NH(2) and 5-HT suggest a role in signaling itch. However, their responsiveness to algogens is inconsistent with itch specificity. Alternatively, such neurons may signal itch, whereas noxious stimulus levels recruit these and a larger population of pruritogen-insensitive cells to signal pain which masks or occludes the itch signal.
| ISSN : | 1529-2401 |
|---|
| Mesh Heading : | Action Potentials Analysis of Variance Animals Behavior, Animal Disease Models, Animal Male Mice Mice, Inbred ICR Oligopeptides Oncogene Proteins v-fos Posterior Horn Cells Pruritus Receptor, PAR-2 Receptors, Cytoplasmic and Nuclear Serotonin Spinal Cord drug effects drug effects pharmacology metabolism metabolism pathology cytology drug effects metabolism |
|---|
| Mesh Heading Relevant : | drug effects chemically induced agonists pharmacology |
|---|
Excitation of mouse superficial dorsal horn neurons by histamine and/or PAR-2 agonist: potential role in itch.
(2009)
Journal - Journal of neurophysiology
Abstract :
Recent studies suggest the existence of separate transduction mechanisms and sensory pathways for histamine and non-histaminergic types of itch. We investigated if histamine and an agonist of the protease-activated receptor (PAR)-2, associated with non-histaminergic itch, excite murine dorsal horn neurons. Single units were recorded in superficial lumbar dorsal horn of adult ICR mice anesthetized with pentobarbital. Unit activity was searched using a small intradermal (id) hindpaw injection of histamine or the PAR-2 agonist SLIGRL-NH2. Isolated units were subsequently challenged with id histamine followed by SLIGRL-NH2 (each 50 microg/1micro l) or reverse order, followed by mechanical, thermal and algogenic stimuli. Forty-three units were classified as wide dynamic range (62%), nociceptive-specific (22%) or mechano-insensitive (16%). Twenty units gave prolonged (mean 10 min) discharges to id injection of histamine; 76% responded to subsequent SLIGRL-NH2, often more briefly. Units additionally responded to noxious heat (63%), cooling (43%), topical mustard oil (53%) and id capsaicin (67%). Twenty-two other units gave prolonged (mean 5 min) responses to initial id injection of SLIGRL-NH2; 85% responded to subsequent id histamine. They also responded to noxious heat (75%), mustard oil (93%), capsaicin (63%), and one to cooling. Most superficial dorsal horn neurons were excited by both histamine and the PAR-2 agonist, suggesting overlapping pathways for histamine- and non-histamine-mediated itch. Since the large majority of pruritogen-responsive neurons also responded to noxious stimuli, itch may be signaled at least partly by a population code.