Peripheral signaling pathways contributing to non-histaminergic itch in humans.

BACKGROUND: Chronic itch (chronic pruritus) is a major therapeutic challenge that remains poorly understood despite the extensive recent analysis of human pruriceptors. It is unclear how the peripheral nervous system differentiates the signaling of non-histaminergic itch and pain. METHODS: Here we used psychophysical analysis and microneurography (single nerve fiber recordings) in healthy human volunteers to explore the distinct signaling mechanisms of itch, using the pruritogens ß-alanine, BAM 8-22 and cowhage extract. RESULTS: The mode of application (injection or focal application using inactivated cowhage spicules) influenced the itch/pain ratio in sensations induced by BAM 8-22 and cowhage but not ß-alanine. We found that sensitizing pre-injections of prostaglandin E2 increased the pain component of BAM 8-22 but not the other pruritogens. A-fibers contributed only to itch induced by ß-alanine. TRPV1 and TRPA1 were necessary for itch signaling induced by all three pruritogens. In single-fiber recordings, we found that BAM 8-22 and ß-alanine injection activated nearly all CM-fibers (to different extents) but not CMi-fibers, whereas cowhage extract injection activated only 56% of CM-fibers but also 25% of CMi-fibers. A "slow bursting discharge pattern" was evoked in 25% of CM-fibers by ß-alanine, in 35% by BAM 8-22, but in only 10% by cowhage extract. CONCLUSION: Our results indicate that no labeled line exists for these pruritogens in humans. A combination of different mechanisms, specific for each pruritogen, leads to itching sensations rather than pain. Notably, non-receptor-based mechanisms such as spatial contrast or discharge pattern coding seem to be important processes. These findings will facilitate the discovery of therapeutic targets for chronic pruritus, which are unlikely to be treated effectively by single receptor blockade.

Cyclic changes of sensory parameters in migraine patients.

BACKGROUND: Migraine shows a cyclic pattern with an inter-ictal-, a pre-ictal, an ictal- and a post-ictal phase. We aimed to examine changes in psychophysical parameters during the migraine cycle. METHODS: The perception of nociceptive and non-nociceptive stimuli and an electrically induced axon-reflex-erythema were assessed in 20 healthy controls and 14 migraine patients on five consecutive days according to different phases of the migraine cycle. Pain was rated three times during a 10-second electrical stimulus. The size of the axon-reflex-erythema was determined using laser-Doppler-imaging. Intensity and hedonic estimates of odours presented by Sniffin' Sticks were rated. RESULTS: In healthy controls, no significant changes over the test days were observed. In migraine patients pain thresholds at the head decreased with an ictal minimum. Less habituation after five seconds of stimulation at the head was found pre-ictally, whereas reduced habituation to 10-second electrical stimulation was present in all phases. The axon-reflex-erythema size showed an inter-ictal-specific minimum at the head. odours were perceived ictally as more unpleasant and intense. CONCLUSIONS: Somatosensory functions, pain thresholds and habituation as predominantly central parameters, axon-reflex-erythema as a peripheral function of trigeminal neurons and odour perception as a predominantly extra-thalamic sensation change specifically over the migraine cycle indicating complex variations of neuronal signal processing.

Lysophosphatidic acid activates nociceptors and causes pain or itch depending on the application mode in human skin.

ABSTRACT: Lysophosphatidic acid (LPA) is involved in the pathophysiology of cholestatic pruritus and neuropathic pain. Slowly conducting peripheral afferent C-nerve fibers are crucial in the sensations of itch and pain. In animal studies, specialized neurons ("pruriceptors") have been described, expressing specific receptors, eg, from the Mas-related G-protein-coupled receptor family. Human nerve fibers involved in pain signaling ("nociceptors") can elicit itch if activated by focalized stimuli such as cowhage spicules. In this study, we scrutinized the effects of LPA in humans by 2 different application modes on the level of psychophysics and single nerve fiber recordings (microneurography). In healthy human subjects, intracutaneous LPA microinjections elicited burning pain, whereas LPA application through inactivated cowhage spicules evoked a moderate itch sensation. Lysophosphatidic acid microinjections induced heat hyperalgesia and hypersensitivity to higher electrical stimulus frequencies. Pharmacological blockade of transient receptor potential channel A1 or transient receptor potential channel vanilloid 1 reduced heat hyperalgesia, but not acute chemical pain. Microneurography revealed an application mode-dependent differential activation of mechanosensitive (CM) and mechanoinsensitive C (CMi) fibers. Lysophosphatidic acid microinjections activated a greater proportion of CMi fibers and more strongly than CM fibers; spicule application of LPA activated CM and CMi fibers to a similar extent but excited CM fibers more and CMi fibers less intensely than microinjections. In conclusion, we show for the first time in humans that LPA can cause pain as well as itch dependent on the mode of application and activates afferent human C fibers. Itch may arise from focal activation of few nerve fibers with distinct spatial contrast to unexcited surrounding afferents and a specific combination of activated fiber subclasses might contribute.

Methylglyoxal causes pain and hyperalgesia in human through C-fiber activation.

The endogenous metabolite methylglyoxal (MG) accumulates in diabetic patients with neuropathic pain. Methylglyoxal could be a mediator of diabetes-induced neuropathic pain through TRPA1 activation and sensitization of the voltage-gated sodium channel subtype 1.8. In this study, we tested the algogenic and sensitizing effect of MG in healthy human subjects using intracutaneous microinjections. The involvement of C fibers was assessed through selective A-fiber nerve block, axon-reflex-erythema, and through single nerve fiber recordings in humans (microneurography). Involvement of the transduction channels TRPA1 and TRPV1 in MG-induced pain sensation was investigated with specific ion channel blockers. We showed for the first time in healthy humans that MG induces pain, axon-reflex-erythema, and long-lasting hyperalgesia through the activation of C nociceptors. Predominantly, the subclass of mechano-insensitive C fibers is activated by MG. A fibers contribute only negligibly to the burning pain sensation. Selective pharmacological blockade of TRPA1 or TRPV1 showed that TRPA1 is crucially involved in MG-induced chemical pain sensation and heat hyperalgesia. In conclusion, the actions of MG through TRPA1 activation on predominantly mechano-insensitive C fibers might be involved in spontaneously perceived pain in diabetic neuropathy and hyperalgesia as well as allodynia.

Cyclic changes in sensations to painful stimuli in migraine patients.

INTRODUCTION: Migraine is characterized by cycling phases (interictal, preictal, ictal and postictal) with differing symptoms, while in chronic tension type headache pain phases are fluctuating. The question we asked is whether these phases are associated with changes in parameters of somatosensation and axon-reflex erythema. METHODS: Patients with episodic migraine and chronic tension type headache were examined psychophysically in the interictal, preictal and ictal phase and healthy subjects on five different test days. Thresholds and suprathreshold ratings of pressure and electrical pain were assessed on three different regions of the head. In migraine patients and in healthy controls, electrically induced axon-reflex erythema was measured in the area of the first trigeminal branch. All migraine patients filled out questionnaires about prodromal symptoms at every visit. RESULTS: The axon-reflex erythema was always larger in patients with migraine in contrast to healthy subjects. The pressure pain threshold was lower in migraine patients and chronic tension type headache in comparison to healthy subjects. Electrical pain thresholds did not differ between headache patients and healthy subjects and showed no changes between the phases. However, suprathreshold pain ratings showed less habituation solely in the preictal phase of migraine. The number of prodromal symptoms in migraine patients was increased in the preictal and ictal phase. DISCUSSION: Reduced habituation was the unique sign of the preictal phase in migraine patients, independently of prodromal symptoms, whereas a larger axon-reflex erythema and higher pressure pain sensitivity are constitutional and non-phase dependent properties of migraine. Reduced inhibitory mechanisms in the preictal phase may contribute to trigger headache attacks in migraine.

Psychological Predictors of Acute Postoperative Pain After Hysterectomy for Benign Causes.

OBJECTIVES: Psychological parameters have been shown to contribute significantly to the development of acute postoperative pain (APOP). For the prediction of APOP in chest malformation patients and cancer patients, we found pain-specific psychological predictors to be of higher relevance than general psychological predictors. The current study aims to further substantiate these findings. MATERIALS AND METHODS: In a sample of 73 middle-aged hysterectomy patients, 3 predictor sets were assessed 1 day before surgery: attentional biases (toward pain-related, social threat, and positive words in a dot-probe task), pain-related emotions and cognitions (pain anxiety, pain catastrophizing, and pain hypervigilance), and affective state variables (depression and somatization). APOP intensity rated 2 to 3 days after surgery and analgesic consumption during the first 48 postoperative hours were used as outcome measures. RESULTS: APOP intensity ratings were significantly explained by their best single predictors in a multiple regression analysis: social threat words of the dot-probe task, pain anxiety, and somatization (14.7% of explained variance). When comparing standardized ß coefficients, pain-specific psychological predictors appeared to be of higher explanatory relevance than general psychological predictors. In contrast, analgesic consumption could not be significantly predicted by the psychological variables. DISCUSSION: Hysterectomy patients at risk for high APOP intensity could be characterized by the psychological variables used, whereas their predictive value for analgesic consumption was limited. The high predictive potency of pain-specific psychological variables should be considered for further improvement of pain management and prevention, because pain-specific variables such as pain anxiety can be the target of focal psychological interventions when preparing for surgery.

Itch induced by a novel method leads to limbic deactivations a functional MRI study.

Functional brain imaging studies on itch usually use histamine as a stimulus and, in consequence, have to cope with the highly variable time course of this particular itch sensation. In this study, we describe a novel method of histamine application. To provoke itch, a mixture of histamine and codeine was applied through intradermally positioned microdialysis fiber. The itch was terminated by lidocaine application through the same fiber. During one fMRI session, this procedure was repeated four times in four different microdialysis fibers, including one placebo control. Itch ratings of the subjects were correlated with blood-oxygen-level-dependent (BOLD) effects. In a subsequent experiment performed in the same fMRI session, heat pain was provoked in the right forearm with a Peltier thermode. During both experiments, activation clusters were found in brain areas that have been described previously to be frequently activated in response to painful stimuli. This includes prefrontal areas, supplementary motor areas (SMA), premotor cortex, anterior insula, anterior midcingulate cortex, S1, S2, thalamus, basal ganglia, and cerebellum. In general, itch stimulation entailed more activation clusters, in particular on the contralateral brain side. Only on itch, but not on heat pain, negative BOLD signals were found in the subgenual anterior cingulate cortex and the amygdala. The latter results may be associated with the itch induced urge to scratch. Amygdala deactivation may be related to the preparation of scratching by aiming to dissolve the otherwise aversive effects of the noxious scratch stimuli. These negative BOLD effects may also be attributed to the stressful character of itch stimulation.