H4 receptor antagonism exhibits anti-nociceptive effects in inflammatory and neuropathic pain models in rats

Hsieh, Gin C.; Chandran, Prasant; Salyers, Anita K.; Pai, Madhavi; Zhu, Chang; Wensink, Erica J.; Witte, David G.; Miller, Thomas R.; Mikusa, Joe; Baker, Scott J.; Wetter, J.; Marsh, Kennan C.; Hancock, Arthur A.; Cowart, Marlon; Esbenshade, Timothy A.; Brioni, Jorge D.; Honoré, Prisca

doi:10.1016/j.pbb.2009.12.004

Cited by 81 publications

(96 citation statements)

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“…These results, indicating the involvement of neuronal H4 receptors in acute thermal antinociception, are in agreement with previous studies reporting the decrease in mechanical hyperalgesia produced by VUF 8430 in a model of neuropathic pain (Smith et al, 2007). However, in contrast with our findings, it has been observed that the systemic administration of the H4 antagonists JNJ7777120 and JNJ 10191584 exhibited anti-hyperalgesic activity in different models of inflammatory pain and anti-allodynic effects in models of neuropathic pain (Coruzzi et al, 2007;Hsieh et al, 2010). This discrepancy might be explained considering that this antihyperalgesic effect is obtained following systemic administration of the H4 antagonists and, as stated by the authors, it appears to be secondary to the anti-inflammatory activity induced by the antagonism of the H4 receptor on immune system cells.…”

Section: Discussionsupporting

confidence: 93%

“…Similarly, the anti-allodynic effect, which is weaker than the antiinflammatory one, origins from the reduction of the inflammatory response at the site of injury in the animal model of neuropathic pain. This hypothesis is further supported by the observations that the H4 antagonist JNJ7777120 did not produce any antinociceptive effect on the contralateral non-inflamed paw (Hsieh et al, 2010). Present results indicate that neuronal histamine H4 receptor activation might be involved in the production of an acute thermal antinociception in the absence of an inflammatory process.…”

Section: Discussionsupporting

confidence: 85%

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

2013

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 85%

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

2013

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“…According to these data, JNJ7777120 reversed hyperalgesia in both acute and chronic pain models (Hsieh et al, 2010a). Notably, in the same study it was found that the H1 receptor antagonist diphenhydramine, H2 receptor antagonist ranitidine or H3 receptor antagonist ABT-239 had no effect on this hyperalgesia, suggesting a dominant role for the H4 receptor in animal models of inflammatory and neuropathic pain.…”

Section: Histamine Neurogenic Inflammation and Nociceptive Painmentioning

confidence: 82%

The role of histamine in neurogenic inflammation

Rosa

Fantozzi

2013

British J Pharmacology

170

138

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The term 'neurogenic inflammation' has been adopted to describe the local release of inflammatory mediators, such as substance P and calcitonin gene-related peptide, from neurons. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. The aim of this review is to summarize the most recent findings on the role of histamine in neurogenic inflammation, with particular regard to nociceptive pain, as well as neurogenic inflammation in the skin, airways and bladder. LINKED ARTICLESThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 Abbreviations CGRP, calcitonin gene-related peptide; ERs, oestrogen receptors; GERD, gastro-oesophageal reflux disease; HDC, histidine decarboxylase; IC, interstitial cystitis; PBS, painful bladder syndrome; SP, substance P; VIP, vasoactive intestinal peptide IntroductionThe term 'neurogenic inflammation' describes the local release of inflammatory mediators, such as substance P (SP) and calcitonin gene-related peptide (CGRP), from afferent neurons. The initial evidence for neurogenic vasodilatation in response to noxious stimuli was obtained in the skin of humans and other mammals (Schmelz and Petersen, 2001), but now it is recognized that neurogenic inflammation also occurs in visceral organs. The inflammatory response evoked by the activation of the sensory nerve fibres, which includes local vasodilatation, plasma extravasation, leukocyte and platelet adhesion, and mast cell degranulation, is brought about by neuropeptides released from the peripheral endings of sensory neurons upon stimulation of the primary sensory terminals. Both SP in neurons and histamine in mast cells have a dual mediator role in neurogenic inflammation (Figure 1). In fact, as demonstrated by Foreman and Jordan (1984), injury causes activation of sensory nerve endings either directly or through the release of histamine from the adjacent mast cells. The action potential generated travels orthodromically to the dorsal horn of the spinal cord and spreads to other branches of the same neurons, which will then release SP from their terminals or varicosities. The released SP, as well as contributing itself to local vasodilatation, induces histamine release from the adjacent mast cells, which produces flare and further activates other sensory nerve endings (Foreman et al., 1983).Neutrophils, whose responsiveness to SP has been repeatedly demonstrated, contribute to the inflammatory soup following neurogenic inflammation. In fact, neutrophils express the SP receptors NK 1, NK2 and NK3, and when stimulated with SP induce the expression of COX-2 and PGE2 release in the nanomolar range (Gallicchio et al., 2008;. Furthermore, SP at micromolar concentrations primes neutrophils, thus en...

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“…Even though the H 4 affinity is lower than the respective H 3 value for all three drugs (Lim et al, 2005), the former may be pharmacologically significant in some cases, especially considering the more recent interest in the H 4 receptor as a target for anti-inflammatory or analgesic drug development (Hsieh et al, 2010a). Initial H 4 receptor research focused on hematopoietic cells (which have the highest receptor densities), but more recent studies have identified the H 4 receptor in the brain (Connelly et al, 2009;Strakhova et al, 2009).…”

Section: Pharmacology Of H 3 R-acting Drugsmentioning

confidence: 99%

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

Hough¹,

Rice²

2010

J Pharmacol Exp Ther

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Histamine H 3 receptors (H 3 Rs), distributed within the brain, the spinal cord, and on specific types of primary sensory neurons, can modulate pain transmission by several mechanisms. In the skin, H 3 Rs are found on certain A␤ fibers, and on keratinocytes and Merkel cells, as well as on deep dermal, peptidergic A␦ fibers terminating on deep dermal blood vessels. Activation of H 3 Rs on the latter in the skin, heart, lung, and dura mater reduces calcitonin gene-related peptide and substance P release, leading to anti-inflammatory (but not antinociceptive) actions. However, activation of H 3 Rs on the spinal terminals of these sensory fibers reduces nociceptive responding to lowintensity mechanical stimuli and inflammatory stimuli such as formalin. These findings suggest that H 3 R agonists might be useful analgesics, but these drugs have not been tested in clinically relevant pain models. Paradoxically, H 3 antagonists/ inverse agonists have also been reported to attenuate several types of pain responses, including phase II responses to formalin. In the periaqueductal gray (an important pain regulatory center), the H 3 inverse agonist thioperamide releases neuronal histamine and mimics histamine's biphasic modulatory effects in thermal nociceptive tests. Newer H 3 inverse agonists with potent, selective, and brain-penetrating properties show efficacy in several neuropathic and arthritis pain models, but the sites and mechanisms for these actions remain poorly understood. Histamine and PainHistamine, found throughout the body in both neuronal and non-neuronal sources, can modify pain transmission by actions at multiple receptors in the skin, spinal cord, and brain. Rapidly expanding information on the distribution and functions of H 3 receptors (H 3 Rs) and the recent development of new H 3 R ligands have heightened interest in the possible modulation of pain by H 3 R-acting drugs. The present article provides a short, integrative overview of relevant studies (for review see also Sander et al., 2008;Tiligada et al., 2009;Gemkow et al., 2009). Measuring Pain in the LaboratoryPain, which can be defined as the central representation of tissue-damaging stimuli with sensory-discriminative, motivational, and cognitive components (Besson and Chaouch, 1987), is readily understood by humans as a sensory experience. Ideally, evaluation of the pain-relieving properties of drugs should directly measure reductions in pain perception. Instead, assessment of analgesic drug action in nonverbal subjects relies heavily on measures of behavioral, often reflexive, responses. Because drugs can modify these responses (but not necessarily the underlying perceptions), results from pain testing in laboratory animals can be misleading. The present limitations of preclinical methodologies for identifying pain-relieving drugs have been discussed previously Vierck et al., 2008).Notwithstanding the limitations in state-of-the-art analgesic testing, many factors must be considered when evaluating

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H4 receptor antagonism exhibits anti-nociceptive effects in inflammatory and neuropathic pain models in rats

Cited by 81 publications

References 65 publications

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

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

The role of histamine in neurogenic inflammation

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

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H4 receptor antagonism exhibits anti-nociceptive effects in inflammatory and neuropathic pain models in rats

Cited by 81 publications

References 65 publications

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

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

The role of histamine in neurogenic inflammation

H3 Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

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H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions