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Venlafaxine has potential as a therapeutic option for patients with depressive disorder, migraine, and pruritus unresponsive to antihistamines.

The contribution of serotonin and noradrenaline to the modulation of pruriceptive processing was evaluated by administrating antidepressants or noradrenaline reuptake inhibitors. The pretreatment with milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, attenuated the induction of scratching behavior by chloroquine, a representative pruritogen, indicating the involvement of serotonin and/or noradrenaline in the modulation of pruriceptive processing. By contrast, the single administration of noradrenaline reuptake inhibitor such as atomoxetine and nisoxetine or serotonin reuptake inhibitor such as fluvoxamine and escitalopram had little effect on chloroquine-induced scratching, whereas the induction of scratching behavior by chloroquine was significantly ameliorated by co-administration of serotonin reuptake inhibitors and noradrenaline reuptake inhibitors. These results indicate that the simultaneous increases of serotonin and noradrenaline elicit the attenuating effect on pruriceptive processing induced by acute itch, and may also play a crucial role in the descending itch inhibitory system.

The roles of serotonin (5-HT) and/or noradrenaline in acute pruriceptive processing have been demonstrated using antidepressants, such as milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant; however, the involvement of 5-HT in acute pruriceptive processing has not yet been elucidated in detail. Scratching events induced by chloroquine (CQ) were attenuated by the administration of milnacipran or mirtazapine, and these effects were reversed by a treatment with ondansetron, a 5-HT

A 63-year-old male receiving hemodialysis for renal insufficiency developed severe and widespread pruritus, which was unresponsive to antihistamines and severe depression with insomnia, agitation, and anxiety. The oral administration of 7.5 mg mirtazapine daily alleviated his severe pruritus after 4 days and severe depression after 14 days. Mirtazapine has potential as a therapeutic option for patients receiving hemodialysis with depressive disorder and severe pruritus unresponsive to antihistamines.

An itch is defined as an unpleasant sensation that evokes a desire to scratch. Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system and has a crucial role in pruriceptive processing in the spinal dorsal horn. It is well known that glutamate exerts its effects by binding to various glutamate receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and that AMPA/kainate receptors play a crucial role in pruriceptive processing; however, the precise role of AMPA receptors remains uncertain. Perampanel, an antiepileptic drug, is an antagonist of AMPA receptors. Pretreatment with perampanel dose-dependently attenuated the induction of scratching, a behavior typically associated with pruritus, by intradermal administration of the pruritogen chloroquine. In addition, the induction of scratching in mice painted with diphenylcyclopropenone and NC/Nga mice treated with Biostir AD, animal models of contact dermatitis and atopic dermatitis, respectively, was dose-dependently alleviated by administration of perampanel. These findings indicate that AMPA receptors play a crucial role in pruriceptive processing in mice with acute or chronic pruritus.

The roles of serotonin (5-HT) and/or noradrenaline in acute pruriceptive processing have been demonstrated using antidepressants, such as milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant; however, the involvement of 5-HT in acute pruriceptive processing has not yet been elucidated in detail. Scratching events induced by chloroquine (CQ) were attenuated by the administration of milnacipran or mirtazapine, and these effects were reversed by a treatment with ondansetron, a 5-HT3 antagonist, or SB26970, a 5-HT7 antagonist. CQ-induced scratching events were also ameliorated by the intrathecal administration of 5-HT, SR572227A and RS56812 (5-HT3 agonists), and LP211 and LP44 (5-HT7 agonists), indicating the modulation of CQ-induced scratching events by 5-HT and noradrenaline. By contrast, histamine-induced scratching events were not markedly affected by the administration of 5-HT and 5-HT7 agonists, whereas 5-HT3 agonists exerted attenuating effects. Similarly, they were not clearly reversed by the administration of the 5-HT7 antagonist, unlike a 5-HT3 antagonist. Therefore, 5-HT is involved in the attenuating effects of milnacipran and mirtazapine on CQ- and histamine-induced scratching events, and 5-HT3 and 5-HT7 receptors play different roles in pruriceptive processing induced by histamine or CQ.

Thalamic pain was first described by Dejerine and Roussy 1 as, “…severe, persistent, paroxysmal, often intolerable, pains on the hemiplegic side, not yielding to any analgesic treatment” 2. Indeed, thalamic pain is characterized by the appearance of constant or intermittent pain in the hemibody, contralateral to the thalamic lesion, and is a severe and treatment‐resistant type of central post‐stroke pain (CPSP) that occurs after a cerebrovascular lesion results in thalamic stroke. Therefore, most of relatively few studies of treatment that have been published cannot claim the gold standard of the randomized, controlled trial 3. Treating CPSP remains a challenge; however, the pharmacological options include antidepressants, antiepileptics, opioids, NMDA‐receptor antagonists, and antiarrhythmics. For example, amitriptyline, a tricyclic antidepressant, is usually used as a drug of first choice for CPSP 4, 5. Nevertheless, the recent evaluated therapies, including amitriptyline, have been largely unsuccessful in controlling CPSP 6, 7, indicating that few options are available for improving CPSP. Central post‐stroke pain is considered to be persistent neuropathic pain of central origin that is generated after stroke. Some anticoagulants and antiplatelets, including triflusal, cilostazol, sarpogrelate, and miscellaneous drugs, may be effective for secondary stroke prevention 8. Cilostazol is also a drug of first choice for intermittent claudication in addition to secondary prevention of cerebral infarction 9, suggesting that the treatment of cilostazol may result in improvement in cerebral infarction. However, there have been no reports on the effects of cilostazol in patients with thalamic pain derived from cerebral infarction. Thus, cilostazol was administered to a patient with both thalamic pain and intermittent claudication, and its effect on thalamic pain was mainly evaluated.

Objective A new mammalian tachykinin peptide encoded in a TAC4 gene was identified and designated as hemokinin-1 (HK-1). A representative of the tachykinin peptide family is substance P (SP), and the function of SP has been well characterized as a pain transmitter or modulator, while it is possible that HK-1 is involved in pruriceptive processing, but, as yet, the distribution of HK-1 peptide in the trigeminal sensory system is still unknown. Thus, the aim of the present study was to elucidate the distribution of HK-1, while comparing the expression of SP, in the trigeminal ganglion and trigeminal sensory nuclear complex. Design The trigeminal ganglion and the brain stem of male SD rats were used in the immunohistochemical study. Since the amino acid sequence in the carboxyl-terminal regions of HK-1 and SP is common, polyclonal antibodies of HK-1 and SP derived from 6 amino acids consisting of amino-terminal regions of these peptides were produced in guinea pig and rabbit, respectively. The immunohistochemical staining of HK-1 and SP was conducted using frozen sections of the trigeminal ganglion and brain stem in rats. Results Immunohistochemical studies revealed the expression of HK-1 in small- and medium-sized trigeminal ganglion neurons, in the paratrigeminal nucleus, and in lamina I of the trigeminal nucleus caudalis, while there was no immunoreactivity of HK-1 in the trigeminal nucleus principalis, trigeminal nucleus oralis, and trigeminal nucleus interpolaris. Conclusion These findings indicate that HK-1 is a target molecule for treatment of itch in the orofaicial regions.

This study proposes a scheme for digital identification of a steel microstructure based on crystallographic features. A 2D space for classifying mixed microstructures of bainite and martensite formed by seven different thermal cycles is defined using two dimensions related to variants in Kurdjumov–Sachs orientation relationships and dislocations. As a dimension relating to variants, the minor variant pair characterized by a rotation axis of 〈011〉 and a rotation angle of 52° is most useful in classifying the steel microstructure. Furthermore, the kernel average misorientation also served as a suitable dimension for the 2D space. The reasons for using the minor variant pair to classify steel microstructures are discussed from the viewpoint of phase transformation phenomena. The present study demonstrates the possibility for steel microstructures to be digitally identified.

The roles of serotonin and noradrenaline in the modulation of chronic pruriceptive processing currently remain unclear. To clarify the contribution of serotonin and noradrenaline to chronic itch, the effects of the administration of antidepressants or noradrenaline reuptake inhibitors were evaluated in the present study. A pretreatment with milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, attenuated the induction of spontaneous scratching behavior in mice with chronic itch. The administration of a serotonin reuptake inhibitor, such as fluvoxamine and paroxetine, but not escitalopram, or a noradrenaline reuptake inhibitor, such as atomoxetine and nisoxetine, ameliorated the induction of spontaneous scratching behavior in mice with chronic itch. Furthermore, this attenuation was reversed by the administration of yohimbine, a selective α2-adrenoceptor antagonist, or methysergide, a non-selective serotonin receptor antagonist. These results suggest that elevated serotonin and noradrenaline levels are involved in the attenuation of scratching behavior induced by chronic itch, and serotonin receptors and an α2-adrenoceptor play a crucial role in chronic pruriceptive processing.

Hemokinin-1 (HK-1) is a member of mammalian tachykinin peptide family, and [Leu11]-HK-1 has an antagonistic effect on HK-1. The attenuation of pruritogen-induced scratching behavior by pretreatment with [Leu11]-HK-1 indicates the involvement of HK-1 in pruriceptive processing. However, it remains unclear whether the intrathecal or intranasal administration of HK-1-derived peptides, such as [D-Trp7,9]-[Leu11]-HK-1 or [D-Trp7]-[Leu11]-HK-1, elicits the effects different from [Leu11]-HK-1. The induction of scratching by intrathecal administration of HK-1 was attenuated 30 min, 4 h and 24 h after pretreatment with [Leu11]-HK-1, [D-Trp7,9]-[Leu11]-HK-1 and [D-Trp7]-[Leu11]-HK-1 or [D-Trp9]-[Leu11]-HK-1, respectively. Similarly, the scratching induced by subcutaneous injection of pruritogens as chloroquine and histamine was ameliorated 30 min and 24 h after pretreatment with [Leu11]-HK-1 and these three HK-1-derived peptides, respectively. Moreover, the effective minimum concentrations of intrathecal administrations of [D-Trp9]-[Leu11]-HK-1 on scratching induced by chloroquine and histamine were 10-6 M, while the effective minimum concentrations of intranasal administration of this peptide on scratching induced by chloroquine and histamine were 10-5 M and 10-4 M, respectively. Thus, the present results indicate that the intrathecal administration of HK-1-derived peptides with D-Trp extends its effective time on scratching induced by intrathecal administration of HK-1 and pruritogens such as chloroquine and histamine. Similarly, the induction of scratching by pruritogens was attenuated by intranasal administration of HK-1-derived peptide, although the effective minimum concentration of this peptide was slightly lower than that of intrathecal administration, indicating that intranasal administration is an effective tool for carrying peptides into the brain.

Cleavage-crack propagation behavior was investigated in the simulated coarse-grained heat-affected zone (CGHAZ) of bainitic steel using electron backscattering diffraction (EBSD) pattern analysis when a low heat input welding was simulated. From viewpoint of crystallographic analysis, it was the condition in which the Bain zone was smaller than the close-packed plane (CP) group. It was clarified that the Bain zone and CP group boundaries provided crack-propagation resistance. The results revealed that when the Bain zone was smaller than the CP group, crack length was about one quarter the size of that measured when the CP group was smaller than the Bain zone because of the increasing Bain-zone boundaries. Furthermore, it was clarified that the plastic work associated with crack opening and resistance at the Bain and CP boundaries could be visualized by the kernel average misorientation maps.

Substance P (SP) is a member of the tachykinin peptide family. Hemokinin-1 (HK-1) was recently identified as a new mammalian tachykinin peptide. SP and HK-1 consist of undecapeptides and share a common carboxyl-terminal (C-terminal), Phe-Xaa-Gly-Leu-Met-amide motif, and more varied amino-terminals (N-terminal). The function of SP in the pain system of the spinal cord has been examined in detail, whereas that of HK-1 remains unclear. Therefore, the effects of [Leu 11 ]-HK-1 on the induction of scratching behavior by the intrathecal administration of HK-1 or SP and scratching behavior by a subcutaneous injection of histamine and serotonin were examined in order to elucidate the function of HK-1. The pretreatment with [Leu 11 ]-HK-1 decreased the induction of scratching behavior by HK-1, but not by SP, while the pretreatment with [Leu 11 ]-SP decreased the induction of scratching behavior by SP, but not by HK-1. Furthermore, the pretreatments with [Leu 11 ]-HK-1 and [Leu 11 ]-SP decreased the frequency of scratching following an intradermal injection of pruritogens, such as serotonin (5-HT) and histamine, into the nape of the neck. The effects of the pretreatment with HK-1 (1-5), an N-terminal fragment peptide, were also examined to determine the function of HK-1. The pretreatment with HK-1 (1-5) attenuated the induction of scratching behavior by HK-1 and SP. In addition, the pretreatment with HK-1 (1-5) attenuated the induction of scratching behavior by a subcutaneous injection of histamine and 5-HT, while the pretreatment with SP (1-5) had a negligible effect on the scratching behavior induced by these compounds. Collectively, these results indicated that HK-1 was involved in pruritic processing because the pretreatment with [Leu 11 ]-HK-1 and HK-1 (1-5) attenuated the induction of scratching behavior by an injection of histamine and 5-HT. Peptide-derived antagonists, such as [Leu 11 ]-HK-1 and HK-1 (1-5), may be unsuitable for the treatment of pruritus because of the difficulties associated with penetrating the blood brain barrier. Therefore, the discovery of chemical compounds that function as antagonists to the HK-1-preferred receptor will become more important in the treatment of pruritic diseases.