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Noradrenergic and opioid systems interact to alter the detection of noxious thermal stimuli and facial scratching in monkeys.

We examined the ability of the alpha 2-adrenoceptor agonist, ST-91, microinjected into the medullary dorsal horn (MDH), to diminish the sensory-discriminative features of noxious heat stimuli in awake behaving monkeys. Two monkeys performed a noxious thermal detection task and the time to detection of small increases in heat served as a measure of the perceived intensity of pain. ST-91 microinjected into the MDH (1.0, 3.0, 10.0 and 30.0 micrograms/0.4 microliter) produced dose-dependent increases in detection time to graded temperature increases (0.4-1.0 degrees C) from a noxious 46 degrees C base line. These dose-dependent effects were attenuated by the systemic administration of the alpha 2-adrenoceptor antagonist, idazoxan (2.0 mg/kg, i.m.), but not by the alpha 1-adrenoceptor antagonist, prazosin (0.5 mg/kg, i.m.) or the opioid-receptor antagonist, naloxone (0.5 mg/kg, i.m.). The effect of ST-91 on detection latency of thermal stimuli was not the result of alterations in attentional, motivational or motoric aspects of the monkeys' behavior, because detection of visual stimuli and non-noxious temperature coolings (36.0-34.5 degrees C) in a similar paradigm were not consistently altered. Microinjection of morphine (3.0 mg) into the MDH also increased detection latency of the noxious heat stimuli. Systemic administration of the opioid-receptor antagonist, naloxone (0.5 mg/kg), and the alpha 2-adrenoceptor antagonist, idazoxan (2.0 mg/kg, i.m.) attenuated these effects of morphine. In a separate experiment, morphine (5.0 micrograms) microinjected into the MDH induced facial scratching behavior. Idazoxan (2.0 mg/kg) was effective at attenuating this scratching behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Antagonists↗

Comparison of activity of individual pyramidal tract neurons during balancing, locomotion, and scratching.

Neuronal mechanisms of the spinal cord, brainstem, and cerebellum play a key role in the control of complex automatic motor behaviors-postural corrections, stepping, and scratching, whereas the role of the motor cortex is less clear. To assess this role, we recorded fore and hind limb-related pyramidal tract neurons (PTNs) in the cat during postural corrections and during locomotion; hind limb PTNs were also tested during scratching. The activity of nearly all PTNs was modulated in the rhythm of each of these motor patterns. The discharge frequency, averaged over the PTN population, was similar in different motor tasks, whereas the degree of frequency modulation was larger during locomotion. In individual PTNs, a correlation between analogous discharge characteristics (frequency or its modulation) in different tasks was very low, suggesting that input signals to PTNs in these tasks have a substantially different origin. In about a half of PTNs, their activity in different tasks was timed to the analogous (flexor/extensor) parts of the cycle, suggesting that these PTNs perform similar functions in these tasks (e.g., control of the value of muscle activity). In another half of PTNs, their activity was timed to opposite parts of the cycle in different tasks. These PTNs seem to perform different motor functions in different tasks, or their targets are active in different parts of the cycle in these tasks, or their effects are not directly related to the control of motor output (e.g., they modulate transmission of afferent signals).

Animals↗

Involvement of substance P in scratching behaviour in an atopic dermatitis model.

Substance P is speculated to be a key mediator of itching in atopic dermatitis, possibly acting via the tachykinin NK1 receptor. Thus, we examined the effect of a tachykinin NK1 antagonist, BIIF 1149 CL, on scratching behaviour in a picrylchloride-induced dermatitis model in NC/Nga mice. BIIF 1149 CL ((S)-N-[2-[3,5-bis(trifluoromethyl) phenyl]ethyl]-4-(cyclopropylmethyl)-N-methyl-alpha-phenyl-1-piperazineacetamide, monohydrochloride, monohydrate) at a dose of 100 mg/kg, p.o., significantly inhibited scratching behaviour immediately after administration, and the effect continued up to 6 h. The results suggest that clinical trials of tachykinin NK1 antagonists for the treatment of itching in atopic dermatitis patients would be warranted.

Animals↗

Kappa opioid agonists suppress chloroquine-induced scratching in mice.

Chemotherapy of malaria fever with chloroquine is often associated with generalized pruritus of unknown pathogenesis. This adverse side effect leads to diminished compliance. We report that chloroquine (1.25-40 mg/kg, s.c.) elicits dose-related, compulsive, and vigorous scratching in mice. This frenzied behavior is essentially abolished when the mice are pretreated s.c. or orally with nalfurafine (TRK-820), a centrally penetrating kappa opioid agonist. Peripheral kappa receptors are involved because chloroquine-induced scratching is also antagonized by the peripherally restricted kappa agonist, ICI 204,448: R,S-N-[2-(N-methyl-3,4-dichlorophenylacetamido)-2-(3-carboxyphenyl) ethyl]pyrrolidine. We propose that combination therapy for malaria with chloroquine and a kappa agonist (probably one targeting peripheral receptors) will lead to better treatment compliance because of a reduced incidence of pruritus.

Analgesics, Opioid↗

The effect of nitrogen diffusion hardening on the surface chemistry and scratch resistance of Ti-6A1-4V alloy.

Modular, head-stem, mixed-metal connections are susceptible to mechanically mediated electrochemical interactions. Any attempt to improve the performance of these connections should center around increasing their resistance to mechanical damage, particularly the titanium alloy (Ti64). This study investigated the effect of a nitrogen-diffusion-hardening process on Ti64, with specific reference to changes in composition, chemistry, electrochemistry and its ability to resist and/or repassivate scratch damage. The nitrogen-diffusion-hardened Ti64 alloy had TiN and TiNO complexes at the immediate surface and sub-surface layers. The diffusion-hardened samples also had a deeper penetration of oxygen compared to regular Ti64 alloy samples. The electrochemical impedance spectroscopy data corroborated the increased thickness of the barrier oxide on the diffusion-hardened samples. The nitrogen-diffusion-hardened samples were more resistant to scratch damage and repaired/repassivated faster after such damage. The results suggest that the nitrogen-diffusion-hardened titanium alloy should exhibit increased resistance to mechanical-electrochemical interactions in mixed-metal modular interfaces in total hip prostheses.

Alloys↗

Pasteurella multocida infection of a total hip arthroplasty following cat scratch.

Pasteurella multocida is a well recognized cause of sepsis following animal contact particularly bites and scratches. Spread to prosthetic joints may occur particularly in immunocompromised patients. Immunocompromised patients with prosthetic joints should be warned that animals are potential sources of serious infection and urgent medical advice should be sought if bitten or scratched.

Animals↗

Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.

BACKGROUND: Intravenous naloxone frequently ameliorates the pruritus of cholestasis, but its low oral bioavailability precludes its use as a long-term therapy. Nalmefene is an orally bioavailable opiate antagonist. OBJECTIVE: We assessed the efficacy of oral nalmefene in ameliorating the pruritus of cholestasis. METHODS: In a prospective controlled study conducted in a tertiary referral hospital, 11 patients with generalized pruritus complicating chronic liver disease were randomized to receive either nalmefene or placebo in a double-blinded fashion for 2-month periods. Scratching activity was measured continuously for 24-hour periods at baseline and at the end of each treatment period. RESULTS: Data on 8 patients who received at least 1 course of nalmefene were available for comparison with corresponding control data, which consisted of observations obtained during a course of placebo and/or at baseline. Nalmefene therapy was associated with a 75% reduction in the geometric mean hourly scratching activity (P <.01) and a decrease in the mean of a visual analogue score of the perception of pruritus in all 8 patients (mean decrease 77%, P <.01). CONCLUSION: Oral administration of nalmefene can ameliorate pruritus complicating chronic liver disease.

Administration, Oral↗

Evidence that N-terminal fragments of nociceptin modulate nociceptin-induced scratching, biting and licking in mice.

The intrathecal (i.t.) injection of 3.0 fmol nociceptin (orphanin FQ) elicited scratching, biting and licking responses in mice. N-terminal fragments of nociceptin, nociceptin (1-7), nociceptin (1-9) and nociceptin (1-13), induced no characteristic behavioral response. When these N-terminal fragments of nociceptin were injected simultaneously with nociceptin, the behavioral response induced by nociceptin was reduced dose-dependently. Nociceptin (1-13) was much more potent than nociceptin (1-7) and nociceptin (1-9) and antagonized nociceptin-induced response at equimolar doses. No significant effects of the N-terminal fragments were observed against the scratching, biting and licking response elicited by i.t. administration of substance P or N-methyl-D-aspartate. These results suggest that N-terminal fragments formed endogenously in the spinal cord may have an antagonistic effect on nociceptin-induced behavioral responses.

Animals↗

Nociceptin-induced scratching, biting and licking in mice: involvement of spinal NK1 receptors.

1. Intrathecal (i.t.) injection of nociceptin at small doses (fmol order) elicited a behavioural response consisting of scratching, biting and licking in conscious mice. Here we have examined the involvement of substance P-containing neurons by using i.t. injection of tachykinin neurokinin (NK)1 receptor antagonists and substance P (SP) antiserum. 2. Nociceptin-induced behavioural response was evoked significantly 5 - 10 min after i.t. injection and reached a maximum at 10 - 15 min. Dose-dependency of the induced response showed a bell-shaped pattern from 0.375 - 30.0 fmol, and the maximum effect was observed at 3.0 fmol. 3. The behavioural response elicited by nociceptin (3.0 fmol) was dose-dependently inhibited by intraperitoneal (i.p.) administration of morphine. 4. The NK1 receptor antagonists, CP-96,345, CP-99,994 and sendide, inhibited nociceptin-induced behavioural response in a dose-dependent manner. A significant antagonistic effect of [D-Phe7, D-His9]SP (6 - 11), a selective antagonist for SP receptors, was observed against nociceptin-induced response. The NK2 receptor antagonist, MEN-10376, had no effect on the response elicited by nociceptin. 5. Pretreatment with SP antiserum resulted in a significant reduction of the response to nociceptin. No significant reduction of nociceptin-induced response was detected in mice pretreated with NKA antiserum. 6. The N-methyl-D-aspartate (NMDA) receptor antagonists, dizocilpine (MK-801) and D(-)-2-amino-5-phosphonovaleric acid (APV) (D-APV), and L-NG-nitro arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, failed to inhibit nociceptin-induced behavioural response. 7. off present results suggest that SP-containing neurons in the mouse spinal cord may be involved in elicitation of scratching, biting and licking behaviour following i.t. injection of nociceptin.

Aggression↗

Scratching and fasting: a study of pruritus and anorexia nervosa.

An association between pruritus and eating disorders has been suggested. This study examined changes in pruritus during weight restoration in a homogeneous group of women with severe anorexia nervosa (n = 19), using a structured questionnaire, visual analogue scale, clinical examination and a range of serological markers. We demonstrated that itching is a clinical feature of anorexia nervosa, associated with low weight and resolving on weight restoration. Some 58% of the sample suffered pruritus at low weight in a stable hospital environment. There was a significant association between changes in body mass index and severity of pruritus (P = 0.033), with reduced itching on weight restoration. Pruritus occurred in the absence of abnormalities in thyroid, renal and hepatic function, serum androgens, oedema, dermatoses or compulsive washing. Scratching was manifest as 'scratch prurigo' in five cases. Where itching was present, it was experienced as severe. We discuss a variety of possible explanations, including psychopathology, endocrine factors, regional blood flow variation, eczema and the role of central opioid and serotonergic activity. We argue that anorexia nervosa should be considered in all patients at low weight presenting with pruritus, and pruritus should be considered to be a physical symptom of anorexia nervosa.

Adult↗

SCRATCH: a protein structure and structural feature prediction server.

SCRATCH is a server for predicting protein tertiary structure and structural features. The SCRATCH software suite includes predictors for secondary structure, relative solvent accessibility, disordered regions, domains, disulfide bridges, single mutation stability, residue contacts versus average, individual residue contacts and tertiary structure. The user simply provides an amino acid sequence and selects the desired predictions, then submits to the server. Results are emailed to the user. The server is available at http://www.igb.uci.edu/servers/psss.html.

Disulfides↗

Intrathecal and systemic R-phenylisopropyl-adenosine reduces scratching behaviour in a rat mononeuropathy model.

The aim of the present study was to investigate the effect of intravenous or intrathecal (i.t.) administration of R-phenylisopropyladenosine (R-PIA), a selective A1 adenosine receptor agonist, on spontaneous scratching behaviour, a phenomenon presumably related to pain in a mononeuropathy model (sciatic nerve ligation) in rats. The acute effect of daily i.t. R-PIA injections was studied up to 21 days following nerve ligation. The results demonstrate that both i.v. (30 nmol) and i.t. (3 nmol) R-PIA, in doses not producing any motor impairment, significantly reduces scratching behaviour in this animal model. The mechanism of action for this presumed antinociceptive effect is suggested to occur at the spinal cord level.

Adenosine↗

The characteristics of patients with atopic dermatitis demonstrating a positive reaction in a scratch test after 48 hours against house dust mite antigen.

The clinical characteristics of patients in whom an IgE-mediated reaction against house dust mite (HDM) antigens that contribute to the pathogenesis of atopic dermatitis (AD) remain unclear. This study attempted to elucidate the characteristics of patients who exhibit a positive reaction 48 hr or later against HDM in scratch tests. The reactions after epi-cutaneous application of the allergen to skin with prior scratching were observed for one week in sixteen AD patients showing positive immediate-type hypersensitivity reactions for HDM. Fifty percent of the patients demonstrated positive reactions at 48 hours after epi-cutaneous application of HDM. Significantly higher values were demonstrated in the group positive for HDM after 48 h in serum total IgE, specific IgE for Der f 1, and lactate dehydrogenase, peripheral eosinophil counts, eruption score, and the area of eruption than in the group negative for HDM after 48 h. Domestic exposure to Der f 1 was also higher in the group positive for HDM after 48 h than in the negative group. These results indicate that the patients in whom the HDM-induced reaction continuing more than 48 h and contributing to their real eczematous eruptions are characterized by considerably increased levels of specific IgE for HDM antigens, high disease activity in AD, and increased exposure to domestic HDM.

Adolescent↗

Further studies of scratching during sleep.

Fifteen patients with a variety of itching skin diseases (atopic eczema, dermatitis herpetiformis, lichen planus, urticaria and psoriasis) have been studied in the sleep laboratory. Recordings were made of all-night electroencephalogram, electro-oculogram, submental electromyogram, and muscle potentials from both forearms. Bouts of scratching during orthodox (NREM) sleep occurred more frequently in stages 1 and 2 than in stages 3 and 4. The frequency in paradoxial (REM) sleep was close to that in stage 2 sleep. This pattern was similar for all the diseases studied and seems to be related to the physiology of the sleep stages rather than to the skin diseases themselves. The mean duration of the bouts of scratching was not related to the sleep stage in which they started.

Dermatitis Herpetiformis↗

Behavioural treatment of scratching in patients with atopic dermatitis.

A behavioural method of habit reversal, in combination with a hydrocortisone cream, was compared with the use of cream alone in the treatment of 17 patients with atopic dermatitis. The patients were assigned randomly to two groups, one of which received the combination treatment and the other regular ointment treatment. The patients' skin status was assessed before and after treatment, and the patients recorded their scratching during the study. Both groups improved, but the group which received habit-reversal therapy improved significantly more. A strong correlation was found between reduction in scratching and improvement in skin status.

Adolescent↗

Parallel reflex pathways from flexor muscle afferents evoking resetting and flexion enhancement during fictive locomotion and scratch in the cat.

Reflex actions of muscle afferents in hindlimb flexor nerves were examined on ipsilateral motoneurone activity recorded in peripheral nerves during midbrain stimulation-evoked fictive locomotion and during fictive scratch in decerebrate cats. Trains of stimuli (15-30 shocks at 200 Hz) were delivered during the flexion phase at intensities sufficient to activate both group I and II afferents (5 times threshold, T). In many preparations tibialis anterior (TA) nerve stimulation terminated ongoing flexion and reset the locomotor cycle to extension (19/31 experiments) while extensor digitorum longus (EDL) stimulation increased and prolonged the ongoing flexor phase activity (20/33 preparations). The effects of sartorius, iliopsoas and peroneus longus muscle afferent stimulation were qualitatively similar to those of EDL nerve. Resetting to extension was seen only with higher intensity stimulation (5T) while ongoing flexor activity was often enhanced at group I intensity (2T) stimulation. The effects of flexor nerve stimulation were qualitatively similar during fictive scratch. Reflex reversals were consistently observed in some fictive locomotor preparations. In those cases, EDL stimulation produced a resetting to extension and TA stimulation prolonged the ongoing flexion phase. Occasionally reflex reversals occurred spontaneously during only one of several stimulus presentations. The variable and opposite actions of flexor afferents on the locomotor step cycle indicate the existence of parallel spinal reflex pathways. A hypothetical organization of reflex pathways from flexor muscle afferents to the spinal pattern generator networks with competing actions of group I and group II afferents on the flexor and extensor portions of this central circuitry is proposed.

Adaptation, Physiological↗

Variations in motor patterns during fictive rostral scratching in the turtle: knee-related deletions.

Agonist motor neurons usually alternate between activity and quiescence during normal rhythmic behavior; antagonist motor neurons are usually active during agonist motor neuron quiescence. During an antagonist deletion, a naturally occurring motor-pattern variation, there is no antagonist activity and no quiescence between successive bursts of agonist activity. Motor neuron recordings of normal fictive rostral scratching in the turtle displayed rhythmic alternation between activity and quiescence for hip flexors, knee flexors, and knee extensors. Knee-flexor activity occurred during knee-extensor quiescence. During a hip-extensor deletion, a variation of rostral scratching, rhythmic hip-flexor bursts occurred without intervening hip-flexor quiescence. There were 3 distinct patterns of knee motor activity during the cycle before or after a hip-extensor deletion. In most cycles, there was knee flexor-extensor rhythmic alternation. In some cycles, termed knee-flexor deletions, there was no knee-flexor activity and rhythmic knee-extensor bursts occurred without intervening knee-extensor quiescence. In other cycles, termed knee-extensor deletions, there was no knee-extensor activity and rhythmic knee-flexor bursts occurred without intervening knee-flexor quiescence. The concept of a module refers to a population of motor neurons and interneurons with similar activity patterns; interneurons in a module coordinate agonist and antagonist motor neuron activities, either with excitation of agonist motor neurons and interneurons, or with inhibition of antagonist motor neurons and interneurons. Previous studies of hip-extensor deletions support the concept of a rhythmogenic hip-flexor module. The knee-related deletions described here support the concept of rhythmogenic knee-flexor and knee-extensor modules linked by reciprocal inhibition.

Animals↗

A high-throughput cell migration assay using scratch wound healing, a comparison of image-based readout methods.

BACKGROUND: Cell migration is a complex phenomenon that requires the coordination of numerous cellular processes. Investigation of cell migration and its underlying biology is of interest to basic scientists and those in search of therapeutics. Current migration assays for screening small molecules, siRNAs, or other perturbations are difficult to perform in parallel at the scale required to screen large libraries. RESULTS: We have adapted the commonly used scratch wound healing assay of tissue-culture cell monolayers to a 384 well plate format. By mechanically scratching the cell substrate with a pin array, we are able to create characteristically sized wounds in all wells of a 384 well plate. Imaging of the healing wounds with an automated fluorescence microscope allows us to distinguish perturbations that affect cell migration, morphology, and division. Readout requires ~1 hr per plate but is high in information content i.e. high content. We compare readouts using different imaging technologies, automated microscopy, scanners and a fluorescence macroscope, and evaluate the trade-off between information content and data acquisition rate. CONCLUSIONS: The adaptation of a wound healing assay to a 384 well format facilitates the study of aspects of cell migration, tissue reorganization, cell division, and other processes that underlie wound healing. This assay allows greater than 10,000 perturbations to be screened per day with a quantitative, high-content readout, and can also be used to characterize small numbers of perturbations in detail.

Actins↗