Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain

Medhurst, Stephen J.; Collins, S D; Billinton, Andy; Bingham, Sharon; Dalziel, Robert; Brass, Amanda; Roberts, Jennifer; Medhurst, Andrew D.; Chessell, Iain P.

doi:10.1016/j.pain.2007.11.006

Cited by 80 publications

(86 citation statements)

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“…Radioligand binding (Pollard et al, 1993;Medhurst et al, 2008), immunohistochemistry (Chazot et al, 2001), and in situ hybridization studies show the existence of H 3 Rs throughout the CNS (Pillot et al, 2002). The highest densities of binding sites were seen in the striatum, cerebral cortex, and olfactory tubercles.…”

Section: Histamine and H 3 Rs In The Nervous Systemmentioning

confidence: 98%

“…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%

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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: 98%

Section: Histamine and H 3 Rs In The Nervous Systemmentioning

confidence: 99%

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

Hough¹,

Rice²

2010

J Pharmacol Exp Ther

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“…164) In contrast to the latter, GSK334429 is a less rigidized 1,4-diazepane possessing comparable properties to that of GSK189254. It is active in attention and cognition models but what is more important, both, GSK189254 and GSK334429, have recently shown to be efficacious in models of neuropathic pain 165) pointing out a possible additive indication for these short-acting and poor brain penetrating ligands as H 3 R modulates pain reception in the dorsal horn and spinal cord 48) (Fig. 7, Tables 1, 2).…”

Section: )mentioning

confidence: 99%

“…However, recent studies on selective H 3 R inverse agonists, GSK189254 and GSK334429, demonstrate efficacy in models of acute and neuropathic pain. 164,165) In this context, autoradiography studies with [ 3 H]GSK189254 show a distinct H 3 R expression pattern in the dorsal horn of human and rat spinal cord and in human dorsal root ganglion. These areas are generally associated with neurochemical processes on nociceptive conduction by cross-linking peripheral and central pathways of sensitisation.…”

Section: )mentioning

confidence: 99%

“…These areas are generally associated with neurochemical processes on nociceptive conduction by cross-linking peripheral and central pathways of sensitisation. 165) For GSK189254 (hH 3 R: pK i ϭ9.9), activity in the peripheral neuronal compartment might be deduced from its low rat brain/blood ratio of 1. Here, the compound is able to increase acetylcholine, dopamine, and noradrenaline levels at the low dosages of 1 mg/kg, perorally administered to rats (ED 50 ϭ0.17 mg/kg).…”

Section: )mentioning

confidence: 99%

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Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

185

118

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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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