Serotonin preferentially hyperpolarizes capsaicin-sensitive C type sensory neurons by activating 5-HT1A receptors

doi:10.1016/0006-8993(92)91209-W

Brain Research

Volume 585, Issues 1–2, 10 July 1992, Pages 212-218

https://doi.org/10.1016/0006-8993(92)91209-W Get rights and content

Abstract

The effects of serotonin (5-HT) were investigated by intracellular recording from 179 dorsal root ganglion (DRG) cells classified by conduction velocity. Bath applied 5-HT depolarized 82% and hyperpolarized 4% of the A-type cells. In C-type cells, 5-HT depolarized only 41%, but hyperpolarized 39% of the cells. The depolarizing responses were of two types; an increase or decrease in R_in, mediated by 5-HT_{2 or 3} receptors, respectively. These receptors were observed in both A- and C-type cells. Hyperpolarizing responses were largely confined to A_delta- and C-type cells. Carboxamidotryptamine and 8-OH-dipropylamino-tetralin were full agonists in eliciting hyperpolarization, and metitepin, spiperone and spiroxitrine behaved as competitive antagonists. This indicated that hyperpolarization was mediated by a 5-HT_1A receptor. A 5-HT_1A&3 receptor were found co-localized on some C-type cells. A strong depolarizing response to capsaicin was observed in the subgroup of C-type neurons that were also hyperpolarized by 5-HT. Thus a co-localization of capsaicin and 5-HT_1A receptors was also observed.

References (36)

P. Bradley et al.
Proposal for classification and nomenclature of functional receptors for 5-hydroxytryptamine
Neuropharmacology
(1986)
E. Carstens et al.
Effects of iontophoretically applied 5-hydroxytryptamine on the excitability of single primary afferent C- and A-fibers in the cat spinal cord
Brain Res.
(1981)
T. Crisp et al.
Analgesic effects of serotonin and receptor-selective serotonin agonists in the rat spinal cord
Gen. Pharmac.
(1991)
G. Daval et al.
Autoradiographic evidence of serotonin-1 binding sites on primary afferent fibers in the dorsal horn of the rat spinal cord
Neurosci. Lett.
(1987)
O.B. Fasmer et al.
Effect of the putative 5-HT_1A receptor agonist 8-OH-2-(dipropylamino) tetralin on nociceptive sensitivity in mice
Pharmac. Biochem. Behav.
(1986)
M. Hamon et al.
Biochemical and autoradiographic evidence of 5-HT₃ receptor binding sites on capsaicin-sensitive fibers in rat spinal cord
Eur. J. Pharmacol.
(1989)
I. Heyman et al.
Depolarizing responses to capsaicin in a subpopulation of rat dorsal root ganglion cells
Neuroscience Letters
(1985)
G.G. Holz et al.
Serotonin depolarizes type A and C primary afferents: an intracellular study in bullfrog dorsal root ganglion
Brain Res.
(1985)
K. Morita et al.
5-hydroxytryptamine effects on the somata of bullfrog primary afferent neurons
Neurosci.
(1987)
D. Nelson et al.
Spiroxitrine: A selective serotonin 1A receptor antagonist
Eur. J. Pharmacol.
(1986)

S. Peroutka

Selective labeling of 5-HT_1A and 5-HT_1B binding sites in bovine brain

Brain Res.

(1985)

H.K. Proudfit et al.

The role of GABA and serotonin in the mediation of raphe-evoked spinal cord dorsal root potentials

Brain Res.

(1980)

J.S. Sprouse et al.

Responses of hippocampal pyramidal cells to putative 5-HT_1A and 5-HT_1B agonists: a comparative study with dorsal raphe neurons

Neuropharmacology

(1988)

S. Todorovic et al.

5-HT₂ and 5-HT₃ receptors mediate two distinct depolarizing responses in rat dorsal root ganglion (DRG) neurones

Brain Research

(1990)

R. Andrade et al.

Pharmacologically distinct actions of serotonin on single neurones of the rat hippocampus recorded in vitro

J. Physiol.

(1987)

J.-M. Beason et al.

Peripheral mechanisms of nociception

Physiol. Rev.

(1987)

S. Bevan et al.

Sensory neuro-specific actions of capsaicin: mechanisms and applications

Trends Pharm. Sci.

(1990)

D.H. Bobker et al.

Serotonin agonists inhibit synaptic potentials in the rat locus ceruleus in vitro via 5-hydroxytryptamine1A and 5-hydroxytryptamine1B receptors

J. Pharm. Exp. Ther.

(1989)

Cited by (56)

The potential role of serotonergic mechanisms in the spinal oxytocin-induced antinociception
2016, Neuropeptides
Citation Excerpt :
We cannot explain this result, but we need to keep in mind that serotonin exerts complex effects, depending on the dose used, and the receptor(s) and neuronal population activated. As previously demonstrated (Todorovic and Anderson, 1992), spinal 5-HT decreases the activity of C-fibers (particularly after 10 min; Fig. 5E, F and H). This inhibition was clearly enhanced by the PVN stimulation when the dose of 5-HT was 50 nmol (Fig. 5H).
The role of oxytocin (OXT) in pain modulation has been suggested. Indeed, hypothalamic paraventricular nuclei (PVN) electrical stimuli reduce the nociceptive neuronal activity (i.e., neuronal discharge associated with activation of Aδ- and C-fibers) of the spinal dorsal horn wide dynamic range (WDR) cells and nociceptive behavior. Furthermore, raphe magnus nuclei lesion reduces the PVN-induced antinociception, suggesting a functional interaction between the OXT and the serotoninergic system. The present study investigated in Wistar rats the potential role of spinal serotonergic mechanisms in the OXT- and PVN-induced antinociception. In long-term secondary mechanical allodynia and hyperalgesia induced by formalin or extracellular unitary recordings of the WDR cells we evaluated the role of 5-hydroxytryptamine (5-HT) effect on the OXT-induced antinociception. All drugs were given intrathecally (i.t.). OXT (1 × 10^− 5–1 × 10^− 4 nmol) or 5-HT (1 × 10^− 3–1 × 10^− 1 nmol) prevented the formalin-induced sensitization, an effect mimicked by PVN stimulation. Moreover, administration of OXT (1 × 10^− 5 nmol) plus 5-HT (1 × 10^− 3 nmol) at ineffective doses, produced antinociception. This effect was antagonized by: (i) d(CH₂)₅[Tyr(Me)²,Thr⁴,Tyr-NH₂⁹]OVT (oxytocin receptor antagonist; 2 × 10^− 2 nmol); or (ii) methiothepin (a non-specific 5-HT_1/2/5/6/7 receptor antagonist; 80 nmol). Similar results were obtained with PVN stimulation plus 5-HT (5 × 10^− 5 nmol). In WDR cell recordings, the PVN-induced antinociception was enhanced by i.t. 5-HT and partly blocked when the spinal cord was pre-treated with methiothepin (80 nmol). Taken together, these results suggest that serotonergic mechanisms at the spinal cord level are partly involved in the OXT-induced antinociception.
Effects of xaliproden, a 5-HT<inf>1A</inf> agonist, on mechanical allodynia caused by chemotherapeutic agents in mice
2013, European Journal of Pharmacology
Citation Excerpt :
Thus, changes in the expression of these channels may be responsible for the oxaliplatin-induced increase of mechanical hypersensitivity of primary afferents. The DRG neurons have been shown to be hyperpolarized by 5-HT1A receptor agonists (Todorovic and Anderson, 1992). In the present study, the mRNA expression of the 5-HT1A receptor was shown in the mouse DRG.
In the present study we investigated whether xaliproden, a selective 5-HT_1A receptor agonist, could relieve allodynia induced by three types of chemotherapeutic agents (paclitaxel, vincristine, and oxaliplatin) in mice. A single intraperitoneal injection of paclitaxel (5 mg/kg), vincristine (0.1 mg/kg), or oxaliplatin (3 mg/kg) time-dependently increased punctate stimulation-evoked allodynia over 10–14 days; the intensities of allodynia were similar between the treatment groups. A single oral dose of xaliproden (0.3–3 mg/kg) inhibited paclitaxel-induced allodynia in a dose-dependent manner. Xaliproden (3 mg/kg) administration produced a slight and no suppression of vincristine-induced and oxaliplatin-induced allodynia, respectively. The firing response of the tibial nerve to punctate stimulation increased in mice that received paclitaxel or oxaliplatin. Xaliproden (3 mg/kg) markedly inhibited the firing response in the mice treated with paclitaxel, while it partially inhibited the firing response in the oxaliplatin-treated animals. Vincristine did not significantly increase the tibial nerve response. Paclitaxel significantly increased the mRNA expression of 5-HT_1A receptor in the dorsal root ganglia, but not in the spinal dorsal horn. In contrast, oxaliplatin significantly increased the mRNA expression of 5-HT_1A receptor in the spinal dorsal horn, but not in the dorsal root ganglia. Vincristine did not affect the mRNA expression of 5-HT_1A receptor in both these regions. These results suggest that xaliproden produces acute inhibition of mechanical allodynia induced by paclitaxel, but not by vincristine and oxaliplatin, via inhibition of the hyper-response of the primary afferent neurons.
Sex differences in the expression of serotonin-synthesizing enzymes in mouse trigeminal ganglia
2011, Neuroscience
Citation Excerpt :
If 5-HT was being released from dural afferents and acting on 5-HT1B or 5-HT1D receptors on blood vessels or sensory nerves then it could ameliorate some of the sensory inputs contributing to migraine in a manner analogous to triptans. However, 5-HT has complex effects on sensory neuron function, acting through a suite of receptors to modulate the activity of potassium channels (Todorovic and Anderson, 1992), calcium channels (Del Mar et al., 1994), tetrodotoxin-resistant sodium channels (Cardenas et al., 1997), the hyperpolarization-activated cation current Ih (Cardenas et al., 1999), TRPV1 (Ohta et al., 2006), and intracellular calcium (Loyd et al., 2011), any of which could act to modulate the excitability of sensory neurons. Within the trigeminal system, the application of 5-HT alone or as part of an “inflammatory soup” sensitizes meningeal nociceptors (Zhang et al., 2007), whereas 5-HT also inhibits primary afferent neurotransmission in the trigeminal dorsal horn (Travagli and Williams, 1996).
Migraine headaches are more prevalent in women and often occur during the early phases of the menstrual cycle, implying a link between migraine and ovarian steroids. Serotonin (5-HT) and its receptors have been proposed to play a key role in the pathophysiology of migraine. The trigeminal ganglion (TG) has been proposed as a site for 5-HT synthesis based on the expression of the rate limiting enzyme in peripheral 5-HT synthesis, tryptophan hydroxylase 1 (TPH1), in female rodent trigeminal ganglia. Tryptophan hydroxylase levels vary over the estrus cycle, however, the expression and potential regulation of other enzymes involved in 5-HT synthesis has not been reported in this tissue. C57/BL6 mice of both sexes expressed TPH1 and aromatic amino acid decarboxylase (AADC), the key enzymes involved in 5-HT synthesis. Levels of both enzymes were significantly higher in juvenile males compared with females. In naturally cycling females TPH1 and AADC expression was highest during proestrus when compared with the other phases of the cycle, and this regulation was mirrored at the mRNA level. In situ hybridization experiments detected TPH1 and AADC mRNA in presumptive neurons in the trigeminal ganglion. Both key enzymes involved in the synthesis of 5-HT are expressed in mouse trigeminal ganglion and are localized to neurons. The levels of these enzymes are dependent on gender and estrus cycle stage, suggesting that ovarian steroids might play a role in the regulation of sensory neuron 5-HT synthesis.
Taltirelin, a thyrotropin-releasing hormone analog, alleviates mechanical allodynia through activation of descending monoaminergic neurons in persistent inflammatory pain
2011, Brain Research
Citation Excerpt :
Application of 5-HT causes hyperpolarization of dorsal horn neurons, which is mimicked by 5-HT1A agonists and blocked by 5-HT1A antagonists (Tan and Mileti, 1992). Furthermore, 5-HT1A agonists hyperpolarize capsaicin-sensitive dorsal root ganglion neurons (Todorovic and Anderson, 1992). Colpaert et al. (2002) reported that 5-HT1A receptor activation reduces allodynia in the inflammation- and nerve-injury-induced persistent pain models.
Thyrotropin-releasing hormone (TRH) and its analogs have been reported to modulate descending monoaminergic inhibitory neurons, resulting in antinociception. However, it remains unknown whether TRH exerts an antiallodynic effect during persistent pain. Here, we investigated the action of taltirelin, a stable TRH analog, on mechanical allodynia in mice with inflammatory persistent pain induced by an injection of complete Freund's adjuvant into the hindpaw. Systemic administration of 1.0 mg/kg taltirelin markedly reduced mechanical allodynia. This effect was abolished by the 6-hydroxydopamine (6-OHDA)-induced depletion of central noradrenaline. While intraperitoneal injection of the α₁-adrenoceptor antagonist prazosin had no effect, intraperitoneal and intrathecal administration of the α₂-adrenoceptor antagonist yohimbine prevented the antiallodynic action of taltirelin. In addition, dl-p-chlorophenylalanine (PCPA)-induced depletion of serotonin (5-HT) and intraperitoneal and intrathecal injection of the 5-HT_1A receptor antagonist WAY-100635 blocked the effect of taltirelin on allodynia. These findings suggest that taltirelin alleviates mechanical allodynia in inflammatory persistent pain by modulating the descending noradrenergic and serotonergic neuronal pathways via indirect activation of spinal α₂-adrenergic and 5-HT_1A receptors.
Reserpine causes biphasic nociceptive sensitivity alteration in conjunction with brain biogenic amine tones in rats
2010, Neuroscience
The present study investigated the precise relationship between brain biogenic amine (dopamine, noradrenaline, and serotonin) tones and nociception. Nociceptive sensitivities to multimodal (muscle pressure, tactile, cold, and heat) stimuli were assessed in acute phase (up to 24 h after reserpine or tetrabenazine injection) and chronic phase (on day 2 or later) in rats. A single injection of reserpine (3 mg/kg s.c.) significantly decreased biogenic amines in the spinal cord (SC), thalamus (THA), and prefrontal cortex (PFC) in both acute and chronic phases, but significantly increased a dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the SC and a serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the SC and THA in acute phase. The content of all biogenic amine metabolites was at low level in chronic phase. Animals exhibited hypersensitivities to tactile and heat stimuli and hyposensitivity to muscle pressure stimulus in acute phase. In chronic phase, they manifested hypersensitivities to all modes of stimuli. Tetrabenazine (20 mg/kg i.p.) significantly decreased brain biogenic amines for a short time, although it did not significantly affect the nociceptive sensitivities. In conclusion, a single injection of reserpine causes a biphasic alteration of nociceptive sensitivities, which is in conjunction with the dynamic change of brain biogenic amine tones, in rats. Cold and heat hypersensitivities in addition to mechanical ones are induced by the reserpine treatment. Sustained modification of brain biogenic amine tones would be critical to induce a robust change in nociceptive sensitivities based on the different effects between reserpine and tetrabenazine.
The role of peripheral 5-HT<inf>1A</inf>, 5-HT<inf>1B</inf>, 5-HT<inf>1D</inf>, 5-HT<inf>1E</inf> and 5-HT<inf>1F</inf> serotonergic receptors in the reduction of nociception in rats
2010, Neuroscience
Citation Excerpt :
These data suggest the presence of 5-HT1A receptors in peripheral terminals of primary sensory afferent fibers. Accordingly, several lines of electrophysiological (Todorovic and Anderson, 1992), pharmacological (Laporte et al., 1995) and molecular biology (Zhang et al., 2002; Liu et al., 2005) evidence suggest that 5-HT1A receptors are present in primary afferent neurons. Our results also agree with a recent study in knock out mice showing that 5-HT1A receptors mediate an endogenous inhibitory control of heat-evoked nociception (Kayser et al., 2007).
This study assessed the possible antinociceptive role of peripheral 5-HT₁ receptor subtypes in the rat formalin test. Rats were injected into the dorsum of the hind paw with 50 μl of diluted formalin (1%). Nociceptive behavior was quantified as the number of flinches of the injected paw. Reduction of flinching was considered as antinociception. Ipsilateral, but not contralateral, peripheral administration of the 5-HT₁ receptor agonists R(+)-UH-301 (5-HT_1A; 0.1–3 μg/paw), CGS-12066A (5-HT_1B; 0.01–0.3 μg/paw), GR46611 (5-HT_1B/1D; 0.3–10 μg/paw), BRL54443 (5-HT_1E/1F; 3–300 μg/paw) or LY344864 (5-HT_1F; 3–300 μg/paw) significantly reduced formalin-induced flinching. The corresponding vehicle was devoid of any effect by itself. The local antinociceptive effect of R(+)-UH-301 (0.3 μg/paw) was significantly reduced by WAY-100635 (30–100 μg/paw; a 5-HT_1A receptor antagonist). Moreover, the antagonists GR55562 (30–100 μg/paw; 5-HT_1B/D) or SB224289 (30–100 μg/paw; 5-HT_1B) dose-dependently reduced the antinociceptive effect of CGS-12066A (0.3 μg/paw) whereas GR55562 (30–100 μg/paw) or BRL15572 (30–100 μg/paw, 5-HT_1D) reduced the antinociceptive effect of GR46611 (0.3 μg/paw). Interestingly, the effects of BRL54443 and LY344864 (300 μg/paw each) were partially reduced by methiothepin, but not by the highest doses of WAY-100635, SB224289 or BRL15572. The above antagonists did not produce any effect by themselves. These results suggest that peripheral activation of the 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1F and, probably, 5-HT_1E receptor subtypes leads to antinociception in the rat formalin test. Thus, the use of selective 5-HT₁ receptor agonists could be a therapeutic strategy to reduce inflammatory pain.

View all citing articles on Scopus

View full text

Serotonin preferentially hyperpolarizes capsaicin-sensitive C type sensory neurons by activating 5-HT1A receptors

Abstract

Neuropharmacology

Brain Res.

Gen. Pharmac.

Neurosci. Lett.

Pharmac. Biochem. Behav.

Eur. J. Pharmacol.

Neuroscience Letters

Brain Res.

Neurosci.

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Neuropharmacology

Brain Research

Pharmacologically distinct actions of serotonin on single neurones of the rat hippocampus recorded in vitro

J. Physiol.

Peripheral mechanisms of nociception

Physiol. Rev.

Sensory neuro-specific actions of capsaicin: mechanisms and applications

Trends Pharm. Sci.

Serotonin agonists inhibit synaptic potentials in the rat locus ceruleus in vitro via 5-hydroxytryptamine1A and 5-hydroxytryptamine1B receptors

J. Pharm. Exp. Ther.

Serotonin preferentially hyperpolarizes capsaicin-sensitive C type sensory neurons by activating 5-HT_1A receptors