Histamine-induced itch and its relationship with pain

Itch is one of the major complications of skin diseases. Although there are various substances that induce itch or pruritus, it is evident that histamine is the best known endogenous agent that evokes itch. Even though histamine-induced itch has been studied for some time, the underlying mechanism of itch is just beginning to emerge. Although various downstream signaling pathways of histamine receptors have been revealed, more studies are required to determine the cause of histamine-induced itch. It appears that itch and pain involve different neuronal pathways. Pain generally inhibits itch, which indicates an inter-communication between the two. Complex interactions between itch and pain may be expected based on reports on disease states and opioids. In this review, we discuss the molecular mechanism and the pharmacological aspects of histamine-induced itch. Especially, the underlying mechanism of TRPV1 (an anti-pruritus target) has been determined to some extent

The role of hypothalamic H1 receptor antagonism in antipsychotic-induced weight gain

Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK—carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity

The waking brain: an update

Wakefulness and consciousness depend on perturbation of the cortical soliloquy. Ascending activation of the cerebral cortex is characteristic for both waking and paradoxical (REM) sleep. These evolutionary conserved activating systems build a network in the brainstem, midbrain, and diencephalon that contains the neurotransmitters and neuromodulators glutamate, histamine, acetylcholine, the catecholamines, serotonin, and some neuropeptides orchestrating the different behavioral states. Inhibition of these waking systems by GABAergic neurons allows sleep. Over the past decades, a prominent role became evident for the histaminergic and the orexinergic neurons as a hypothalamic waking center

Histaminergic system in brain disorders: lessons from the translational approach and future perspectives

Histamine and its receptors were first described as part of immune and gastrointestinal systems, but their presence in the central nervous system and importance in behavior are gaining more attention. The histaminergic system modulates different processes including wakefulness, feeding, and learning and memory consolidation. Histamine receptors (H1R, H2R, H3R, and H4R) belong to the rhodopsin-like family of G protein-coupled receptors, present constitutive activity, and are subjected to inverse agonist action. The involvement of the histaminergic system in brain disorders, such as Alzheimer’s disease, schizophrenia, sleep disorders, drug dependence, and Parkinson’s disease, is largely studied. Data obtained from preclinical studies point antagonists of histamine receptors as promising alternatives to treat brain disorders. Thus, clinical trials are currently ongoing to assess the effects of these drugs on humans. This review summarizes the role of histaminergic system in brain disorders, as well as the effects of different histamine antagonists on animal models and humans

Expression of a cloned rat histamine H2 receptor mediating inhibition of arachidonate release and activation of cAMP accumulation.

A DNA, cloned after screening a rat genomic bank with probes derived from the sequence of a putative dog histamine H2 receptor [Gantz, I., Schäffer, M., Delvalle, J., Logsdon, C., Campbell, V., Uhler, M. & Yamada, T. (1991) Proc. Natl. Acad. Sci. USA 88, 429-433], was used to prepare a probe for Northern blot analysis and to transfect Chinese hamster ovary (CHO) cells. Distribution of the gene transcripts in guinea pig tissues was consistent with that of H2 receptors. Transfected CHO cells expressed a high density of sites binding [125I]iodoaminopotentidine, a selective H2-receptor ligand. These sites were characterized as typical H2 receptors by using a series of competing agents that displayed apparent dissociation constants closely similar to corresponding values at a reference biological system. In transfected cells, histamine stimulated, with high potency and large receptor reserve, the accumulation of cAMP. In addition, in the same cells, histamine potently inhibited the release of arachidonic acid induced either by stimulation of constitutive purinergic receptors or by application of a Ca2+ ionophore. This inhibition was independent of either cAMP or Ca2+ levels. The results suggest that a single H2 receptor may be linked not only to adenylyl cyclase activation but also to reduction of phospholipase A2 activity. Because H1 receptors have been reported to stimulate arachidonic acid release, inhibition of this release, an unexpected signaling pathway for H2 receptors, may account for the opposing physiological responses elicited in many tissues by stimulation of these two receptors subtypes

Arachidonate 5-lipoxygenase and its activating protein: prominent hippocampal expression and role in somatostatin signaling.

5-Lipoxygenase-activating protein (FLAP) is an 18-kDa integral membrane protein required, in peripheral cells, for the activation of 5-lipoxygenase (5-LO) and for the resulting synthesis of leukotrienes from arachidonic acid. In the brain, the leukotrienes have been implicated in several pathophysiological events and in the electrophysiological effect of somatostatin, yet the cellular origin and role of these messenger molecules are still poorly understood. In the present study, we used reverse transcriptase-polymerase chain reaction, in situ hybridization, and immunohistochemistry to demonstrate that 5-LO and FLAP are expressed in various regions of the rat brain, including hippocampus, cerebellum, primary olfactory cortex, superficial neocortex, thalamus, hypothalamus, and brainstem. Highest levels of expression were observed in cerebellum and hippocampus. In the latter we demonstrate the colocalization of 5-LO and FLAP in CA1 pyramidal neurons. Moreover, electrophysiological experiments show that selective inhibition of FLAP with the compound MK-886 (0.25-1 microM) prevents the somatostatin-induced augmentation of the hippocampal K+ M-current. Our results provide necessary evidence for the presence and signaling role of 5-LO and FLAP in central neurons and strongly support their proposed participation in somatostatin-receptor transmembrane signaling

Arachidonate 5-lipoxygenase and its activating protein: prominent hippocampal expression and role in somatostatin signaling.

5-Lipoxygenase-activating protein (FLAP) is an 18-kDa integral membrane protein required, in peripheral cells, for the activation of 5-lipoxygenase (5-LO) and for the resulting synthesis of leukotrienes from arachidonic acid. In the brain, the leukotrienes have been implicated in several pathophysiological events and in the electrophysiological effect of somatostatin, yet the cellular origin and role of these messenger molecules are still poorly understood. In the present study, we used reverse transcriptase-polymerase chain reaction, in situ hybridization, and immunohistochemistry to demonstrate that 5-LO and FLAP are expressed in various regions of the rat brain, including hippocampus, cerebellum, primary olfactory cortex, superficial neocortex, thalamus, hypothalamus, and brainstem. Highest levels of expression were observed in cerebellum and hippocampus. In the latter we demonstrate the colocalization of 5-LO and FLAP in CA1 pyramidal neurons. Moreover, electrophysiological experiments show that selective inhibition of FLAP with the compound MK-886 (0.25-1 microM) prevents the somatostatin-induced augmentation of the hippocampal K+ M-current. Our results provide necessary evidence for the presence and signaling role of 5-LO and FLAP in central neurons and strongly support their proposed participation in somatostatin-receptor transmembrane signaling