Key points * Voltage-gated sodium channels play a fundamental role in determining neuronal excitability. * Specifically, voltage-gated sodium channel subtype Na sub(V)1.7 is required for sensing ...acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown. * Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for Na sub(V)1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling. * These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality-specific manner and help to direct drug discovery efforts towards novel visceral analgesics. Voltage-gated sodium channel Na sub(V)1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of Na sub(V)1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific Na sub(V)1.7 knockout mouse (Na sub(V)1.7 super(Nav1.8)) and selective small-molecule Na sub(V)1.7 antagonist PF-5198007. Na sub(V)1.7 super(Nav1.8) mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both Na sub(V)1.7 super(Nav1.8) and littermate controls. Loss, or blockade, of Na sub(V)1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of Na sub(V)1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel alpha subunits revealed Na sub(V)1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of Na sub(V)1.7 (in Na sub(V)1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective Na sub(V)1.7 antagonist PF-5198007. Our data demonstrate that Na sub(V)1.7 (in Na sub(V)1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of Na sub(V)1.7 alone in the viscera may be insufficient in targeting chronic visceral pain. Key points * Voltage-gated sodium channels play a fundamental role in determining neuronal excitability. * Specifically, voltage-gated sodium channel subtype Na sub(V)1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown. * Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for Na sub(V)1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling. * These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality-specific manner and help to direct drug discovery efforts towards novel visceral analgesics.
Approaches to the treatment of visceral pain Bulmer, David C.E; Coelho, Anne-Marie; Winchester, Wendy J
Drug discovery today. Therapeutic strategies,
09/2007, Letnik:
4, Številka:
3
Journal Article
Recenzirano
Great advances have been made in the past decade in our understanding of visceral pain, in particular irritable bowel syndrome (IBS). As a consequence of these breakthroughs, a number of ...mechanistically differing, therapeutic treatments are currently available or in clinical trials. Experimental medicine studies on compounds in development provide favourable early indications that these therapies may show efficacy for the treatment of visceral pain and suggest a promising future for many patients that currently suffer with visceral pain syndromes.
Background & Aims:
Although the β
3-adrenoceptor (AR) has been suggested to be involved in regulation of gut motility and visceral algesia, the precise mechanisms have been unknown. β
3-AR has been ...postulated to have a nonneuronal expression, being initially characterized in adipocytes and subsequently in the smooth muscle. We aimed to investigate the expression of β
3-AR in human enteric nervous system and its role in motility and visceral algesia.
Methods:
The expression of β
3-AR in human colon myenteric and submucosal plexus was investigated using immunohistochemistry. The effects of a β
3-AR agonist on nerve-evoked and carbachol-induced contractions as well as somatostatin release were investigated in strips of human colon. The effect of an agonist on diarrhea and visceral pain was investigated in vivo in rat models.
Results:
β
3-AR is expressed in cholinergic neurons in the myenteric plexus and submucosal plexus of human colon. Activation of β
3-AR causes the release of somatostatin from human isolated colon. In a rat model of visceral pain, β
3-AR agonist elicits somatostatin-dependent visceral analgesia. β
3-AR agonists inhibit cholinergically mediated muscle contraction of the human colon, as well as chemically induced diarrhea in vivo in a rat model.
Conclusions:
This is the first demonstration of expression of β
3-AR in the enteric nervous system. Activation of these receptors results in inhibition of cholinergic contractions and enhanced release of somatostatin, which may lead to visceral analgesia and inhibition of diarrhea. Therefore, β
3-AR could be a novel therapeutic target for functional gastrointestinal disorders.
KEY POINTSVoltage-gated sodium channels play a fundamental role in determining neuronal excitability. Specifically, voltage-gated sodium channel subtype NaV 1.7 is required for sensing acute and ...inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown. Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV 1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling. These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality-specific manner and help to direct drug discovery efforts towards novel visceral analgesics. ABSTRACTVoltage-gated sodium channel NaV 1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of NaV 1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific NaV 1.7 knockout mouse (NaV 1.7Nav1.8 ) and selective small-molecule NaV 1.7 antagonist PF-5198007. NaV 1.7Nav1.8 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both NaV 1.7Nav1.8 and littermate controls. Loss, or blockade, of NaV 1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of NaV 1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed NaV 1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of NaV 1.7 (in NaV 1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective NaV 1.7 antagonist PF-5198007. Our data demonstrate that NaV 1.7 (in NaV 1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of NaV 1.7 alone in the viscera may be insufficient in targeting chronic visceral pain.
Despite its beneficial effect in IBS patients, the mechanism of action of the 5-HT
3 receptor (5-HT
3R) antagonist alosetron is still incompletely understood. We aimed to characterize the effect and ...site(s) of action in a model of stress-induced sensitization of visceral nociception in rats. Adult male Wistar rats were equipped for recording of visceromotor response (VMR) to phasic colorectal distension (CRD; 10–60
mm
Hg). VMR to CRD was recorded 24
h after an acute session of water avoidance (WA) stress (post-WA). Baseline and post-WA responses were measured in rats exposed to WA or sham-WA, treated with alosetron at 0.3
mg/kg subcutaneously (s.c.) 25
nmol intrathecally (i.t.) or vehicle before post-WA CRD. Some rats were treated with capsaicin/vehicle on the cervical vagus nerve and received alosetron (0.3
mg/kg, s.c.) 15
min before post-WA CRD. WA stress led to visceral hyperalgesia 24
h later. Alosetron (0.3
mg/kg, s.c.), failed to inhibit WA-induced exacerbation of VMR to CRD. Stress-induced visceral hyperalgesia was abolished when alosetron was injected intrathecally (
P
<
0.05) in intact rats or subcutaneously (0.3
mg/kg) in capsaicin-pretreated animals (
P
<
0.05). Capsaicin-pretreatment did not affect the exacerbating effect of stress on visceral sensitivity. Alosetron had no inhibitory effect on normal visceral pain responses when administered subcutaneously or intrathecally. We demonstrated that 5-HT
3Rs on central terminals of spinal afferents are engaged in the facilitatory effect of stress on visceral sensory information processing. In addition, we showed that stress-induced sensitization of visceral nociception is independent of 5-HT
3R activation on vagal afferents.
This paper details the discovery and characterization of GSK345931 (
7i) from the lead compound
4.
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the ...EP
1 receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative
4 which displayed molecular weight of 414.9
g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound
7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9
g/mol). In addition,
7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
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