Central neuronal functions of histamine H4 receptors

The human histamine H 4 receptor (H 4 R), the most recently discovered histamine receptor, is predominantly expressed on inflammatory cells and lymphoid tissues and characterized as the immune system histamine receptor with a pro-inflammatory role. The occurrence of H 4 R on human and rodent neurons has also been recently reported, but, conversely to the well-characterized immunological role of the peripheral H 4 R, much less is known about its functions in the central nervous system (CNS). The expression and neuronal role of H 4 R has been controversially discussed since its discovery. The human and rat H 4 R mRNA and protein were detected in dorsal root ganglia (DRG), spinal cord and several brain regions [1, 2], but the difficulty to generate H 4 R antibodies with high specificity generates results that should be interpreted with some caution. Some indication for a functional role in the CNS for this receptor came from studies with selective ligands [3, 4]. However, in the absence of knockout controls, off-target effects of the H 4 R ligands cannot be fully excluded. Although H 4 R-deficient mice were generated more than a decade ago, they have not been used to elucidate the physiopathological role of this receptor subtype in the CNS. The study of Sanna et al. [5] is the first investigation on the functional role of neuronal H 4 R through the characterization of the behavioural phenotype of H 4 R-deficient mice. Authors [6] showed that a prominent role of neuronal H 4 R appears to be the modulation of pain perception. In human and rodents, expression of H 4 R mRNA is the highest in the spinal cord and H 4 R protein is strongly expressed in sensory neurons of DRG and in the lumbar spinal cord, especially laminae I and II [1, 2], consistent with a role of H 4 R in pain perception. Conversely to what expected from the pro-nociceptive profile obtained by peripheral H 4 R stimulation, H 4 R-deficient mice had unaltered sensitivity to thermal and mechanical stimuli, and showed increased pain hypersensitivity in the presence of a peripheral neuropathy. This hypernociceptive phenotype indicates an involvement of neuronal H 4 R in the response to a condition of pathological chronic pain of neuronal origin rather than in the regulation of the physiological maintenance of the pain threshold. A dual role of neuronal and peripheral H 4 R …


Maria Domenica Sanna and Nicoletta Galeotti
The human histamine H 4 receptor (H 4 R), the most recently discovered histamine receptor, is predominantly expressed on inflammatory cells and lymphoid tissues and characterized as the immune system histamine receptor with a pro-inflammatory role. The occurrence of H 4 R on human and rodent neurons has also been recently reported, but, conversely to the well-characterized immunological role of the peripheral H 4 R, much less is known about its functions in the central nervous system (CNS).
The expression and neuronal role of H 4 R has been controversially discussed since its discovery. The human and rat H 4 R mRNA and protein were detected in dorsal root ganglia (DRG), spinal cord and several brain regions [1,2], but the difficulty to generate H 4 R antibodies with high specificity generates results that should be interpreted with some caution. Some indication for a functional role in the CNS for this receptor came from studies with selective ligands [3,4]. However, in the absence of knockout controls, off-target effects of the H 4 R ligands cannot be fully excluded. Although H 4 R-deficient mice were generated more than a decade ago, they have not been used to elucidate the physiopathological role of this receptor subtype in the CNS. The study of Sanna et al. [5] is the first investigation on the functional role of neuronal H 4 R through the characterization of the behavioural phenotype of H 4 R-deficient mice.
Authors [6] showed that a prominent role of neuronal H 4 R appears to be the modulation of pain perception. In human and rodents, expression of H 4 R mRNA is the highest in the spinal cord and H 4 R protein is strongly expressed in sensory neurons of DRG and in the lumbar spinal cord, especially laminae I and II [1,2], consistent with a role of H 4 R in pain perception. Conversely to what expected from the pro-nociceptive profile obtained by peripheral H 4 R stimulation, H 4 R-deficient mice had unaltered sensitivity to thermal and mechanical stimuli, and showed increased pain hypersensitivity in the presence of a peripheral neuropathy. This hypernociceptive phenotype indicates an involvement of neuronal H 4 R in the response to a condition of pathological chronic pain of neuronal origin rather than in the regulation of the physiological maintenance of the pain threshold. A dual role of neuronal and peripheral H 4 R on pain processes can be postulated: pain-reducing activity by neuronal H 4 R stimulation, pain-promoting pro-inflammatory effects by peripheral H 4 R stimulation.
A role of the histaminergic system in the modulation of anxiety has been suggested, but investigations produced contradictory results and opposite roles for histamine H 1 R, H 2 R and H 3 R subtypes have been reported [6]. H 4 R deficiency exacerbated the response to an anxietyprovoking environment. This anxiogenic-like phenotype of H 4 R-deficient mice indicates a positive effect of neuronal H 4 R stimulation on anxiety management. This hypothesis was supported by the anxiolytic-like effects produced by centrally administered H 4 R agonists in behavioural tasks in mice [4].
Brain histamine plays a fundamental role in eating behaviour and induces loss of appetite and suppression of food intake mainly via H 1 R [6]. H 4 R-deficient mice showed an increase in food intake, consistent with the reduction of food consumption observed after intracerebroventricular administration of the H 4 R full agonist VUF 8430. Neuronal H 4 R might, thus, exert a synergic action with H 1 R in the histaminergic regulation of eating behaviour.
The histaminergic system is known to be involved in the regulation of locomotor activity. Histidine decarboxylase, H 1 R, H 2 R and H 3 R knockout mice showed reduced locomotor activity [7]. Conversely, behavioural characterization of H 4 R-deficient mice showed an increase in ambulation in an open field and in exploratory activity, revealing an increased spontaneous locomotor activity. These findings highlight a role of H 4 R on motor behaviour at odds with that observed for the other histamine receptor subtypes.
The study of Sanna et al. [6] illustrated a peculiar and selective behavioural profile of H 4 R-deficient mice with a modest or absent involvement of H 4 R in some of neuronal functions modulated by the histaminergic system, such as depression and memory. Pharmacological or genetic loss of histamine or histamine receptor function in animals produces phenotypes that model human depression [6]. H 4 R-deficient mice had higher immobility time than wild type mice in a behavioural despair paradigm, showing a depressant-like response. However, in the same testing environment, central administration of H 4 R agonists was devoid of any antidepressant-like activity, suggesting a minor role of H 4 R in depression. Authors observed that H 4 R deficiency induces an anxiogenic-like behaviour and the increased immobility time recorded might be a response to an anxiety-promoting environment rather than a depressant-like response. Findings on H 4 R-deficient mice also exclude an outstanding role of H 4 R in the histaminergic modulation of memory processes. Although histaminergic neurons project to regions important for Editorial: Neuroscience cognitive functions, H 4 R-deficient mice did not show any alteration of both working and recognition memory.
Characterization of the behavioural phenotype of H 4 R-deficient mice assessed a functional role of neuronal H 4 R and highlighted the importance of its integrity in the histaminergic regulation of important neurophysiological functions, including pain sensitivity and anxiety. Since the identification of H 4 R, several ligands activating this receptor have been described and more compounds are in development. Targeting neuronal H 4 R with selective agonists might be a clinical relevant therapeutic approach to be exploited to relieve neuropathic pain and to better manage anxiety and anxiety-related disorders.