Secondary mechanical allodynia and hyperalgesia depend on descending facilitation mediated by spinal 5-HT4, 5-HT6 and 5-HT7 receptors

Godínez‐Chaparro, Beatriz; López-Santillán, Francisco J.; Orduña, Patricia; Granados‐Soto, Vinicio

doi:10.1016/j.neuroscience.2012.07.008

Cited by 37 publications

(28 citation statements)

References 97 publications

(158 reference statements)

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“…This contralateral hypersensitivity has been previously reported and may be a result of spinal cord sensitization or changes higher brain centers and the descending pain system[2, 17]. Although mechanical hypersensitivity after formalin has been observed in female rats[25], to our knowledge, our data are the first demonstration of this pain-like response in female mice at 180 min.…”

Section: Discussionsupporting

confidence: 75%

Hormonal and molecular effects of restraint stress on formalin-induced pain-like behavior in male and female mice

Long

Sadler

Kolber

2016

Physiology & Behavior

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The evolutionary advantages to the suppression of pain during a stressful event (stress-induced analgesia (SIA)) are obvious, yet the reasoning behind sex-differences in the expression of this pain reduction are not. The different ways in which males and females integrate physiological stress responses and descending pain inhibition are unclear. A potential supraspinal modulator of stress-induced analgesia is the central nucleus of the amygdala (CeA). This limbic brain region is involved in both the processing of stress and pain; the CeA is anatomically and molecularly linked to regions of the hypothalamic pituitary adrenal (HPA) axis and descending pain network. The CeA exhibits sex-based differences in response to stress and pain that may differentially induce SIA in males and females. Here, sex-based differences in behavioral and molecular indices of SIA were examined following noxious stimulation. Acute restraint stress in male and female mice was performed prior to intraplantar injections of formalin, a noxious inflammatory agent. Spontaneous pain-like behaviors were measured for 60 min following formalin injection and mechanical hypersensitivity was evaluated 120 and 180 min post-injection. Restraint stress altered formalin-induced spontaneous behaviors in male and female mice and formalin-induced mechanical hypersensitivity in male mice. To assess molecular indices of SIA, tissue samples from the CeA and blood samples were collected at the 180 min time point. Restraint stress prevented formalin-induced increases in extracellular signal regulated kinase 2 (ERK2) phosphorylation in the male CeA, but no changes associated with pERK2 were seen with formalin or restraint in females. Sex differences were also seen in plasma corticosterone concentrations 180 min post injection. These results demonstrate sex-based differences in behavioral, molecular, and hormonal indices of acute stress in mice that extend for 180 min after stress and noxious stimulation.

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Section: Discussionsupporting

confidence: 75%

Hormonal and molecular effects of restraint stress on formalin-induced pain-like behavior in male and female mice

Long

Sadler

Kolber

2016

Physiology & Behavior

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“…Adenylate cyclase is activated by G s -protein-coupled receptors. In DRG neurons, G-protein-coupled receptors, such as PAR2, DP1, IP, EP2, EP4, CGRP, PACAP, and 5-HT 4 receptors, have been shown to couple with G s (Jongsma et al, 2000;Segond von Banchet et al, 2002;Ossovskaya and Bunnett, 2004;Moriyama et al, 2005;Ebersberger et al, 2011;Godínez-Chaparro et al, 2012;Yokoyama et al, 2013;Ma and St-Jacques, 2018). Among their antagonists, only the EP4 receptor antagonist CJ-023423 (3 mM) significantly inhibited the increase in I h current in ipsilateral neurons with diameters of 40-50 mm (N 5 5-7 for each group) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Prostanoid EP4 Receptor-Mediated Augmentation of I_h Currents in Aβ Dorsal Root Ganglion Neurons Underlies Neuropathic Pain

Zhang

Kashihara

Nakada

et al. 2018

J Pharmacol Exp Ther

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An injury of the somatosensory system causes neuropathic pain, which is usually refractory to conventional analgesics, thus warranting the development of novel drugs against this kind of pain. The mechanism of neuropathic pain in rats that had undergone left L5 spinal nerve transection was analyzed. Ten days after surgery, these rats acquired neuropathic pain. The patch-clamp technique was used on the isolated bilateral L5 dorsal root ganglion neurons. The current-clamped neurons on the ipsilateral side exhibited significantly higher excitability than those on the contralateral side. However, only neurons with diameters of 40-50 mm on the ipsilateral side exhibited significantly larger voltage sags in response to hyperpolarizing current pulses than those on the contralateral side. Under the voltage clamp, only these neurons on the ipsilateral side showed a significantly larger density of an inward current at , 280 mV [hyperpolarization-activated nonselective cation (I h) current] with a rightward-shifted activation curve than that on the contralateral side. Ivabradine-an I h current inhibitor-inhibited I h currents in these neurons on both sides in a similar concentrationdependent manner, with an IC 50 value of ∼3 mM. Moreover, the oral administration of ivabradine significantly alleviated the neuropathic pain on the ipsilateral side. An inhibitor of adenylyl cyclase or an antagonist of prostanoid EP4 receptors (CJ-023423) inhibited ipsilateral, but not contralateral I h , currents in these neurons. Furthermore, the intrathecal administration of CJ-023423 significantly attenuated neuropathic pain on the ipsilateral side. Thus, ivabradine and/or CJ-023423 may be a lead compound for the development of novel therapeutics against neuropathic pain.

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“…63 This pronociceptive effect of 5 was confirmed by the same group using formalin-induced secondary allodynia and hyperalgesia in rats. 64,65 Of interest, when considering the significant affinity of this compound for 5-HT 3 R, the pronociceptive activity demonstrated in these three studies was significantly reduced by the injection of the 5-HT 6 R antagonist 24 (SB-399885) or 25 (SB-258585). This confirms that 5-HT 6 R is involved in this pharmacological action.…”

Section: Preclinical Interest Of 5-ht 6 R Activationmentioning

confidence: 98%

Therapeutic Potential of 5-HT₆ Receptor Agonists

et al. 2015

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Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox.

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Secondary mechanical allodynia and hyperalgesia depend on descending facilitation mediated by spinal 5-HT4, 5-HT6 and 5-HT7 receptors

Cited by 37 publications

References 97 publications

Hormonal and molecular effects of restraint stress on formalin-induced pain-like behavior in male and female mice

Hormonal and molecular effects of restraint stress on formalin-induced pain-like behavior in male and female mice

Prostanoid EP4 Receptor-Mediated Augmentation of I_h Currents in Aβ Dorsal Root Ganglion Neurons Underlies Neuropathic Pain

Therapeutic Potential of 5-HT₆ Receptor Agonists

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Secondary mechanical allodynia and hyperalgesia depend on descending facilitation mediated by spinal 5-HT4, 5-HT6 and 5-HT7 receptors

Cited by 37 publications

References 97 publications

Hormonal and molecular effects of restraint stress on formalin-induced pain-like behavior in male and female mice

Hormonal and molecular effects of restraint stress on formalin-induced pain-like behavior in male and female mice

Prostanoid EP4 Receptor-Mediated Augmentation of Ih Currents in Aβ Dorsal Root Ganglion Neurons Underlies Neuropathic Pain

Therapeutic Potential of 5-HT6 Receptor Agonists

Contact Info

Product

Resources

About

Prostanoid EP4 Receptor-Mediated Augmentation of I_h Currents in Aβ Dorsal Root Ganglion Neurons Underlies Neuropathic Pain

Therapeutic Potential of 5-HT₆ Receptor Agonists