Regulation of substance P release mediated via prejunctional histamine H3 receptors

Ohkubo, Tsuyako; Shibata, Manabu; Inoue, M.; Kaya, Hidehiro; Takahashi, Hiroshi

doi:10.1016/0014-2999(94)00668-w

Cited by 80 publications

(48 citation statements)

References 20 publications

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“…Early measurements of inflammatory peptide release suggested that H 3 Rs are present on sensory nerves (Delaunois et al, 1995;Ohkubo et al, 1995;Imamura et al, 1996;Rouleau et al, 1997;Poveda et al, 2006), but the localization of H 3 Rs within the peripheral nervous system and spinal cord (Pollard et al, 1993;Héron et al, 2001;Medhurst et al, 2008) was only recently confirmed by immunohistochemistry (Cannon et al, 2007a). In rat and mouse skin, H 3 R-like immunoreactivity (H 3 RLI) was absent in all of the thin-caliber epidermal and superficial dermal innervation, but present in a subset of thin-caliber fibers associated with arterioles in the deep dermis (Fig.…”

Section: Histamine and H 3 Rs In The Nervous Systemmentioning

confidence: 99%

“…Although these components may be related to pain, the distribution of H 3 Rs on classically defined pain fibers is limited to the deep dermal perivascular A␦ fibers, which are closely associated with blood vessels. In the skin, activation of H 3 Rs on peptidergic A␦ fibers presumably suppresses neuropeptide release and attenuates inflammation-related edema (Ohkubo et al, 1995). In the spinal cord, activation of H 3 Rs reduces nociceptive responses elicited by low-intensity mechanical stimulation (Cannon et al, 2003) and proinflammatory agents such as formalin (Cannon et al, 2007b).…”

Section: Formalin-induced Nociceptionmentioning

confidence: 99%

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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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Section: Histamine and H 3 Rs In The Nervous Systemmentioning

confidence: 99%

Section: Formalin-induced Nociceptionmentioning

confidence: 99%

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

Hough¹,

Rice²

2010

J Pharmacol Exp Ther

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“…28) H 3 R expression is not solely restricted to histaminergic neurons: due to its function as a heteroreceptor it can be found on colocalised neurons, and H 3 R activation modulates the release of various important neurotransmitters, i.e. dopamine, [29][30][31][32][33] acetylcholine, [34][35][36][37] norepinephrine, 38,39) serotonin, 40,41) GABA, [42][43][44] glutamate, 45) and substance P. [46][47][48] Therefore, histaminergic neurons and the cross-linkage between major neurotransmitter systems are involved in many (patho)physiological brain functions, including vigilance, memory processes, feeding behaviour and locomotor activity (Fig. 2).…”

Section: Auto-and Heteroreceptormentioning

confidence: 99%

Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

184

116

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INTRODUCTIONThe biogenic amine histamine, 2-(1H-imidazol-4-yl)-ethanamine, is produced by decarboxylation of L-histidine and is implicated in a wide range of physiological and pathophysiological functions. It is metabolised by histamine N tmethyltransferase (HMT) and mono-or diaminoxidase. Histamine is mainly acting via four distinct metabotropic histamine receptor subtypes (H 1 R-H 4 R), which have meanwhile all been cloned. Whereas antagonists for H 1 R and H 2 R subtypes have been blockbusters in therapy of allergy and ulcer, respectively, antagonists for H 3 R and H 4 R subtypes are not on the market. The recently described H 4 R seems to be involved in inflammatory and immunomodulatory processes. H 3 Rs play a central role in neurotransmission of histamine and in control of many other neurotransmitters. Several antagonists are in preclinical and some in clinical stage of development. PHARMACOLOGICAL BACKGROUND Auto-and HeteroreceptorThe H 3 R was first described in 1983 as a presynaptic autoreceptor, which mediates synthesis of histamine and inhibition of its release from histaminergic neurons in slices of rat cerebral cortex. 1) Localisation studies in rodents show a predominance in distinct regions of the central nervous system (CNS) as the H 3 R is mainly located in cerebral cortex, hippocampus, amygdala, nucleus accumbens, globus pallidus, striatum, and hypothalamus 2-5) ( Fig. 1). In addition, it is expressed in the peripheral nervous system, e.g. in gastrointestinal tract, airways and cardiovascular system. 6) Molecular aspects of the receptor, [7][8][9][10] structure-activity relationships (SAR) of ligands, [11][12][13][14][15][16][17][18][19] and pharmacology [20][21][22][23][24][25][26] have recently been resumed in many excellent reviews. This contribution focuses on the development of clinical candidates and the multifaceted potential indications targeted.In mammalian brain histaminergic neurons originate in the tuberomammillary nucleus (TMN) spreading into above mentioned brain regions, where they control histamine levels by regulation of synthesis and liberation rates 27) and modulate different neuronal systems. 28) H 3 R expression is not solely restricted to histaminergic neurons: due to its function as a heteroreceptor it can be found on colocalised neurons, and H 3 R activation modulates the release of various important neurotransmitters, i.e. dopamine, [29][30][31][32][33] acetylcholine, [34][35][36][37] norepinephrine, 38,39) serotonin, 40,41) GABA, [42][43][44] glutamate, 45) and substance P. [46][47][48] Therefore, histaminergic neurons and the cross-linkage between major neurotransmitter systems are involved in many (patho)physiological brain functions, including vigilance, memory processes, feeding behaviour and locomotor activity (Fig. 2). Interneuron cross-talk and adaptive processes seem to be important factors in H 3 Rmediated signalling. Molecular AspectsThe human histamine H 3 receptor (hH 3 R) cDNA firstly described 1999 encodes a 445 amino acid protein and belongs to the his...

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“…The histamine H 3 receptors in the central nervous system appear to be present primarily on nerve terminals, where they regulate not only histamine release but also the release of other neurotransmitters such as acetylcholine, dopamine, noradrenaline, and serotonin (2). It has been suggested that in the periphery, the receptors may exist in the perivascular nerve terminals (3) and that they could also control the release of various chemical mediators such as substance P (4).…”

Section: Introductionmentioning

confidence: 99%

Role of Substance P on Histamine H3 Antagonist-Induced Scratching Behavior in Mice

et al. 2006

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Abstract. The purpose of the present study was to investigate the involvement of chemical mediators, other than histamine, in the scratching behavior induced by H 3 antagonists. Scratching behavior was induced by the histamine H 3 antagonists iodophenpropit and clobenpropit (10 nmol / site) when they were injected intradermally into the rostral part of the back of mastcell-deficient (WBB6F1 W / W v ) and wild-type (WBB6F1 +/ +) mice. Subsequently, the effect of spantide, a tachykinin NK 1 antagonist, was measured for 60 min. The effects of the H 3 antagonists on in vitro histamine release from rat peritoneal mast cells were also investigated. When spantide was injected intradermally at a dose of 0.5 nmol / site, it significantly inhibited the response. Furthermore, iodophenpropit and clobenpropit (10 −6 -10 −8 M) did not induce histamine release in isolated rat peritoneal mast cells. Our results indicate that substance P is involved in the skin responses elicited by the histamine H 3 antagonists. Moreover, the fact that these histamine H 3 antagonists did not induce significant increases in the histamine release from rat peritoneal mast cells suggests that the histamine H 3 receptor may not be present in the peripheral cells considered in this study.

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Regulation of substance P release mediated via prejunctional histamine H3 receptors

Cited by 80 publications

References 20 publications

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

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

Histamine H3 Receptor Antagonists Go to Clinics

Role of Substance P on Histamine H3 Antagonist-Induced Scratching Behavior in Mice

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Regulation of substance P release mediated via prejunctional histamine H3 receptors

Cited by 80 publications

References 20 publications

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

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

Histamine H3 Receptor Antagonists Go to Clinics

Role of Substance P on Histamine H3 Antagonist-Induced Scratching Behavior in Mice

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Product

Resources

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

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