Contribution of the peripheral 5-HT2A receptor to mechanical hyperalgesia in a rat model of neuropathic pain

Nitanda, Aya; Yasunami, Naho; Tokumo, Kohji; Fujii, Hiromitsu; Hanabusa, Takao; Nishio, Hiroaki

doi:10.1016/j.neuint.2005.06.002

Cited by 52 publications

(20 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This shaking behavior typically manifests as a vibration-like shaking of the hindpaw in the air and is an indicator of spontaneous pain similar to symptoms commonly described in patients with neuropathic pain [55,56]. The data from the present study corroborate previous findings demonstrating that CCI is a useful tool for investigating the neurobiology of neuropathic pain [34,57,58]. As described above, predator exposure is an innately aversive stimulus that evokes defensive responses [1,6,7] and, like other aversionbased tests, it can induce antinociception [17,18,25,41,42,47].…”

Section: Discussionsupporting

confidence: 89%

Rat exposure in mice with neuropathic pain induces fear and antinociception that is not reversed by 5-HT2C receptor activation in the dorsal periaqueductal gray

Furuya-da-Cunha

Souza

Canto-de-Souza

2016

Behavioural Brain Research

View full text Add to dashboard Cite

Previous studies have demonstrated that serotonin 5-HT2C receptors in the dorsal periaqueductal gray (dPAG) mediate both anxiety and antinociception in mice submitted to the elevated plus maze. The present study examined the effects of intra-dPAG infusion of the serotonin 5-HT2C receptor agonist (MK-212) in the defensive reactions and antinociception in mice with neurophatic pain confronted by a predator. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve, and predator confrontation was performed using the rat exposure test (RET). Our results demonstrated that both sham-operated and CCI mice exhibited intense defensive reactions when confronted by rats. However, rat-exposed CCI mice showed reduced pain reactivity in comparison to CCI mice exposed to a toy rat. Intra-dPAG infusion of MK-212 prior to predator exposure did not significantly alter defensive or antinociceptive responses. To our knowledge, our results represent the first evidence of RET-induced antinociception in mice. Moreover, the results of the present study suggest that 5-HT2C receptor activation in the dPAG is not critically involved in the control of predator-evoked fearful or antinociceptive responses.

show abstract

Section: Discussionsupporting

confidence: 89%

Rat exposure in mice with neuropathic pain induces fear and antinociception that is not reversed by 5-HT2C receptor activation in the dorsal periaqueductal gray

Furuya-da-Cunha

Souza

Canto-de-Souza

2016

Behavioural Brain Research

View full text Add to dashboard Cite

show abstract

“…In addition, direct injection of duloxetine or DOI into the paw of diabetic rats produced a slight decrease of PWT in the first hour after administration. Our data implicate activation of peripheral 5‐HT 2A receptors in the allodynia of diabetic rats and are in agreement with the reported excitatory role of the peripheral 5‐HT 2A receptor in other pain modality models such as neuropathic or inflammatory pain models (Obata et al ., 2000; Sasaki et al ., 2001; Okamoto et al ., 2002; Nitanda et al ., 2005). The peripheral sources of 5‐HT include mast cells, platelets and endothelial cells (Dray, 1995; Millan, 1999), while 5‐HT 2A receptors are located on endothelial cells (Martin, 1994), Schwann cells (Yoder et al ., 1997; Gaietta et al ., 2003), the perikarya of sensory neurons in the DRG (Okamoto et al ., 2002; Van Steenwinckel et al ., 2009), and in axons of both myelinated and unmyelinated fibres (Carlton and Coggeshall, 1997; Okamoto et al ., 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Studies in animal models suggest that the nature of the involvement of the 5‐HT 2A receptor may be location specific. Indeed, neuropathic pain is reported to be alleviated by both activation of spinal 5‐HT 2A receptors and systemic administration of the 5‐HT 2A receptor antagonist ketanserin (Obata et al ., 2001; Nitanda et al ., 2005; Honda et al ., 2006).…”

Section: Introductionmentioning

confidence: 99%

A spinal mechanism of action for duloxetine in a rat model of painful diabetic neuropathy

Mixcoatl-Zecuatl

Jolivalt²

2011

British Journal of Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSEThis study was designed to clarify mechanisms responsible for the anti-allodynic effects of duloxetine in diabetes. EXPERIMENTAL APPROACHThe streptozotocin-induced diabetic rat model was used to compare the efficacy of duloxetine, 5-HT, the 5-HT2A receptor agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)] and two antagonists (ketanserin and pruvanserin) on tactile allodynia. KEY RESULTSSystemic or intrathecal injection of duloxetine alleviated tactile allodynia in diabetic rats. The effect of systemic duloxetine was reduced by intrathecal administration of ketanserin or pruvanserin, indicating participation of spinal 5-HT2A receptors in the mechanism of action of duloxetine. In contrast to spinal delivery, systemic and local peripheral injections of ketanserin or pruvanserin alleviated tactile allodynia in diabetic rats. This effect was reversed immediately after systemic or local DOI injection. CONCLUSIONS AND IMPLICATIONSThese results support the involvement of spinal 5-HT2A receptors in the ability of duloxetine to ameliorate painful diabetic neuropathy. Our data also suggest that the role of 5-HT2A receptors depends on the level of the neuraxis at which activation takes place, with peripheral activation contributing to tactile allodynia in diabetic rats, whereas spinal activation of this receptor alleviates tactile allodynia. The development of selective peripheral 5-HT2A receptor antagonists may offer a novel approach for the treatment of diabetic neuropathic pain. AbbreviationsAUC, area under the 50% PWT time curve; ECL, enhanced chemiluminescence; DOI, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride; DRG, dorsal root ganglia; i.t., intrathecal; PBS, phosphate buffered saline buffer; PWT, paw withdrawal threshold IntroductionDiabetes mellitus is an increasingly common chronic medical condition, affecting over 100 million people worldwide. Up to 60% of diabetic patients develop some form of peripheral neuropathy and around 20% will develop neuropathic pain, including spontaneous pain, paresthesia, dysethesia, hyperalgesia and allodynia (Boulton et al., 1983;Partanen et al., 1995). The current first-line treatments for painful diabetic neuropathy include anticonvulsants, tricyclic antidepressants, opioids and serotonin (5-HT) and noradrenaline reuptake inhibitors (Ziegler, 2009). Duloxetine (Cymbalta) is a 5-HT-noradrenaline reuptake inhibitor used to treat depression that also alleviates allodynia in several inflammatory and neuropathic pain models (Iyengar et al., 2004 Piesla et al., 2009;Vranken et al., 2011). Clinical studies have confirmed the efficacy of duloxetine against pain in diabetic patients (Goldstein et al., 2005;Raskin et al., 2005;Wernicke et al., 2006), and the drug has been approved by the US Food and Drug Administration for management of painful diabetic neuropathy. The sites and mechanisms of action responsible for the pain-relieving effects of duloxetine in diabetes remain unclear. Duloxetine inhibits transporters of 5-HT and n...

show abstract

“…As demonstrated earlier, 5‐HT 2A receptor antagonists have an analgesic effect on inflammatory pain (Nitanda et al, ; Cervantes‐Duran et al, ). In the present study, we demonstrated the inhibitory effect of a 5‐HT 2A antagonist on the visceral pain response in non‐inflammatory models (Bourdu et al, ).…”

Section: Discussionmentioning

confidence: 55%

Ameliorative effect of chlorpromazine hydrochloride on visceral hypersensitivity in rats: possible involvement of 5‐HT_2A receptor

Asano

Tanaka

Tada

et al. 2017

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSEVisceral hypersensitivity is responsible for pathogenesis of irritable bowel syndrome (IBS). Therefore, its prevention can help avoid abdominal pain and discomfort in IBS. To find candidate drugs for visceral hypersensitivity, we screened existing medicines for their ability to prevent visceral sensitivity induced by colorectal distension (CRD) in rats and identified chlorpromazine, a typical antipsychotic drug, as a candidate compound. In this study, we investigated the effect of chlorpromazine on visceral hypersensitivity. EXPERIMENTAL APPROACHVisceral sensitivity (visceromotor response) was monitored by measuring the electrical activity of the abdominal external oblique muscle contraction in response to CRD using a barostat apparatus. Visceral hypersensitivity was induced by a colonic instillation of sodium butyrate or acetic acid in neonates. KEY RESULTSOral administration of chlorpromazine suppressed butyrate-induced visceral hypersensitivity to CRD. Interestingly, atypical antipsychotic drugs, quetiapine and risperidone, ameliorated butyrate-induced visceral hypersensitivity, whereas the typical antipsychotic drugs, haloperidol and sulpiride, did not. Pharmacological analysis using specific inhibitors showed that a selective 5-HT 2A receptor antagonist, ketanserin, suppressed butyrate-induced visceral hypersensitivity, whereas a selective dopamine D 2 receptor antagonist, L-741626, did not. Furthermore, the 5-HT 2A receptor agonist AL-34662 stimulated visceral sensitivity to CRD in healthy control rats but not in butyrate-treated rats. These findings suggest that increased 5-HT levels in the colon contribute to the induction of visceral hypersensitivity. CONCLUSIONS AND IMPLICATIONSOur results indicate that chlorpromazine ameliorates visceral hypersensitivity and that the 5-HT 2A receptor is a potential therapeutic target for treating abdominal pain and discomfort in IBS. Abbreviations7OH-Cpz, 7-hydroxy chlorpromazine; ASIC, acid-sensing ion channel; CRD, colorectal distension; DRG, dorsal root ganglion; IBS, irritable bowel syndrome; p-CPA, p-chlorphenylalanine; TRPV1, transient receptor potential vanilloid 1; VMR, visceromotor response

show abstract

Contribution of the peripheral 5-HT2A receptor to mechanical hyperalgesia in a rat model of neuropathic pain

Cited by 52 publications

References 19 publications

Rat exposure in mice with neuropathic pain induces fear and antinociception that is not reversed by 5-HT2C receptor activation in the dorsal periaqueductal gray

Rat exposure in mice with neuropathic pain induces fear and antinociception that is not reversed by 5-HT2C receptor activation in the dorsal periaqueductal gray

A spinal mechanism of action for duloxetine in a rat model of painful diabetic neuropathy

Ameliorative effect of chlorpromazine hydrochloride on visceral hypersensitivity in rats: possible involvement of 5‐HT_2A receptor

Contact Info

Product

Resources

About

Contribution of the peripheral 5-HT2A receptor to mechanical hyperalgesia in a rat model of neuropathic pain

Cited by 52 publications

References 19 publications

Rat exposure in mice with neuropathic pain induces fear and antinociception that is not reversed by 5-HT2C receptor activation in the dorsal periaqueductal gray

Rat exposure in mice with neuropathic pain induces fear and antinociception that is not reversed by 5-HT2C receptor activation in the dorsal periaqueductal gray

A spinal mechanism of action for duloxetine in a rat model of painful diabetic neuropathy

Ameliorative effect of chlorpromazine hydrochloride on visceral hypersensitivity in rats: possible involvement of 5‐HT2A receptor

Contact Info

Product

Resources

About

Ameliorative effect of chlorpromazine hydrochloride on visceral hypersensitivity in rats: possible involvement of 5‐HT_2A receptor