Pleiotropic effect of histamine H4 receptor modulation in the central nervous system

Abstract

a b s t r a c tThe histamine H4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses. Recently, it has been reported the functional expression of H4R within neurons of the central nervous system, but their role has been poorly understood. The present study aimed to elucidate the physiopathological role of cerebral H4R in animal models by the intracerebroventricular administration of the H4R agonist VUF 8430 (20e40 mg per mouse). Selectivity of results was confirmed by the prevention of the effects produced by the H4R antagonist JNJ 10191584 (3e9 mg/kg p.o.). Neuronal H4R activation induced acute thermal antinociception, indicating that neuronal histamine H4R might be involved in the production of antinociception in the absence of an inflammatory process. An anxiolyticlike effect of intensity comparable to that exerted by diazepam, used as reference drug, was produced in the lightedark box test. VUF 8430 reversed the scopolamine-induced amnesia in the passive avoidance test and showed anorexant activity in food deprived mice. Conversely, the H4R activation did not modify the immobility time in the tail suspension test. Rotarod performance test was employed to demonstrate that the effects observed following the administration of VUF 8430 and JNJ 10191584 were not due to impaired motor function of animals. Furthermore, both compounds did not alter spontaneous mobility and exploratory activity in the hole board test. These results show the antinociceptive, antiamnesic, anxiolytic and anorexant effects induced by neuronal H4R agonism, suggesting that H4 modulators may have broader utility further the control of inflammatory and immune processes.

The histamine H4-receptor and the central and peripheral nervous system: A critical analysis of the literature

“…Central function of H 4 R was also suggested in a study reporting on behavioral effects of H 4 R activation (Galeotti et al, 2013). The intracerebroventricular application of the H 4 R agonist VUF 8430 produced antinociceptive, anxiolytic, antiamnesic and anorectic effects in Swiss albino mice (Galeotti et al, 2013) that were sensitive to the H 4 R antagonist JNJ 10191584.…”

“…The H 4 R antagonist JNJ 7777120 (s.c. injection) increased mechanical hyperalgesia in a rat neuropathic pain model (partial sciatic nerve ligation), while an s.c. injection of the H 4 R agonist VUF 8430 exhibited an antinociceptive effect (Smith et al, 2007). In a mouse model, VUF 8430 (i.c.v administration) increased the thermal pain threshold, and this effect was antagonized by oral pre-treatment with the H 4 R antagonist JNJ 10191584 (Galeotti et al, 2013). Thus, H 4 R stimulation seems to exhibit pain-reducing antinociceptive effects.…”

“…The intracerebroventricular application of the H 4 R agonist VUF 8430 produced antinociceptive, anxiolytic, antiamnesic and anorectic effects in Swiss albino mice (Galeotti et al, 2013) that were sensitive to the H 4 R antagonist JNJ 10191584. However, no knockout controls were used in this study and therefore off-target effects of the H 4 R ligands cannot be fully excluded.…”

“…The discrepancy between pro-and antiallodynic effects of H 4 R blockade may be explained by modelspecific differences. As discussed by Galeotti et al (2013), on the one hand, H 4 R antagonists may exhibit anti-hyperalgesic effects that are secondary to anti-inflammatory activity. On the other hand activation of neuronal H 4 R may result in antinociceptive effects in the absence of inflammation (Galeotti et al, 2013).…”

Neuronal effects of a nickel-piperazine/NO donor complex in rodents

“…The performance time was measured before and at various times after treatment [24]. The number of falls within 30 s was also detected [25].…”