Pronociceptive effect of 5-HT1A receptor agonist on visceral pain involves spinal N-methyl-d-aspartate (NMDA) receptor
Highlights
► 5-HT1A receptor agonist DPAT produces pronociceptive effects in visceral pain. ► DPAT activates of presynaptic 5-HT1A receptors to inhibit GABA release. ► Inhibition of GABAergic neurons unmasks the excitatory glutamatergic system. ► This effect results in visceral hyperalgesia in behavioral studies. ► The electrophysiology experiments also confirm the findings of behavioral studies.
Introduction
5-HT1, a negative G-protein (Gi/Go)-coupled serotonin (5-HT) receptor, plays diverse and complex functions including cognition, emotion (fear and rage) and pain modulation (Millan and Colpaert, 1990, Millan et al., 1996, Kayser et al., 2007). Of five subclasses (5-HT1A, B, D, E, F), 5-HT1A is the most prevalent receptor in CNS. The specific binding of [3H]-8-hydroxy-2-(di-n-propylamino) tetralin ([3H]-DPAT), a 5-HT1A receptor agonist, was detected in several regions of the rat brain. The major binding sites were found in the cortex, hippocampus, striatum, periaqueductal gray (PAG), rostroventral medulla (RVM) and spinal cord (Gozlan et al., 1983, Hall et al., 1985, Viisanen and Pertovaara, 2010). Although 5-HT1A receptors are present both at pre- and post-synaptic sites, in some areas including the spinal cord the expression is predominantly at pre-synaptic sites. This pre-synaptic location of the receptor has complicated autoreceptor functions that regulate the release of specific neurotransmitters to modulate neuronal functions. For example, studies have documented that 5-HT1A expressing neurons in the midbrain and spinal cord play a significant role in pain modulation by regulating the opioid release (Millan and Colpaert, 1990, Millan and Colpaert, 1991, Millan et al., 1996, Song et al., 2007). In the rat spinal cord, 5-HT1A receptors are the major subclass accounting for 30–50% of the total population of 5-HT1 (i.e., 5-HT1A–F) and are primarily concentrated in the superficial laminae (I, III and IV) (Huang and Peroutka, 1987, Thor et al., 1990, Marlier et al., 1991, Laporte et al., 1996). The receptor exhibits a rapid increase in the expression under pathological conditions including peripheral inflammation and spinal cord injury (Zhang et al., 2002, Otoshi et al., 2009). Some studies indicate that the activation of 5-HT1A receptors in the spinal cord and midbrain results in somatic antinociception (Gillet et al., 1985, Eide et al., 1988, El-Yassir et al., 1988, Giordano, 1989, El-Yassir and Fleetwood-Walker, 1990, Eide and Hole, 1991, Giordano and Rogers, 1992, Eide and Hole, 1993, Galeotti et al., 1997, Xu et al., 1994, Oyama et al., 1996, Gjerstad et al., 1996, Xiao et al., 2005, Wei and Pertovaara, 2006), whereas other studies report pronociceptive effect (Solomon and Gebhart, 1988, Zemlan et al., 1988, Crisp et al., 1991a, Crisp et al., 1991b, Alhaider and Wilcox, 1993, Ali et al., 1994, Zhang et al., 2001). Similarly, in the rodent model of visceral pain while one study indicates that the partial 5-HT1A receptor agonist buspirone produces analgesia to noxious colon distension (Sivarao et al., 2004), a recent report indicates that 5-HT1A antagonists (WAY-100635 and AZD7371) produce visceral analgesia in the same species (Lindström et al., 2009). Although these conflicting results are difficult to explain, it could be related to the subjective nature (visual estimate of abdominal contraction) of pain scoring; the strain of rats used and most importantly the physiological condition of the animal.
The objective of the present study was to examine the mechanism and the site of action of a selective 5-HT1A receptor agonist DPAT in the rat model of visceral pain. We hypothesize that the pronociceptive effect of DPAT is due to activation of negative G-protein (Gi/Go)-coupled 5-HT1A receptor located at the presynaptic terminals of GABAergic interneurons that results in hyperpolarization of cells and the reduction of γ-amino butyric acid (GABA) release. Since GABA primarily acts as an inhibitory neurotransmitter in the spinal cord and modulates the functions of excitatory glutamatergic neurons, the reduction of GABA release will disinhibit these neurons to produce hyperexcitation of spinal dorsal horn neurons resulting in visceral hyperalgesia.
Section snippets
Animals
The study was carried out in male Sprague–Dawley rats (Harlan, Indianapolis, IN, USA) weighing about 400 g (range: 350–450 g). All experimental procedures were performed according to approved guidelines of The Institutional Animal Care and Use committee at the Medical College of Wisconsin (approval # AUA0000356) and the International Association for the Study of Pain (IASP).
Surgery for recording viscero-motor response (VMR)
All surgical procedures were performed in adult rats anesthetized with sodium pentobarbital (45–50 mg/kg, i.p., Ovation
Effect of DPAT on VMR to CRD
A systemic injection of DPAT increased the VMR to CRD (Fig. 1). Low dose (5 μg/kg, i.p., n = 6) of DPAT increased the VMR significantly (p < 0.05 vs. baseline) at distending pressure ⩾30 mmHg (Fig. 1A, n = 6). However, at higher doses (50 and 250 μg/kg, i.p., n = 6 and 7, respectively) the VMR increased significantly (p < 0.05 vs. baseline) at much lower distension pressure (∼10 mmHg) (Fig 1B, C). There were no dose-dependent differences in VMRs between 50 and 250 μg/kg. Therefore, in subsequent experiments,
Discussion
In the present study, we have systematically examined the mechanism of action of the 5-HT1A receptor agonist DPAT and the site of action of the drug. The results indicate that the drug produces visceral pronociceptive effects by unmasking the action of excitatory glutamatergic neurons at the spinal level. The effect of the drug is most likely due to activation of 5-HT1A, a negative G-protein (Gi/Go)-coupled receptor located at presynaptic terminals of inhibitory GABAergic interneurons. This
Conflict of interest statement
None of the contributing authors have any conflict of interest. All authors are in agreement with the content of this manuscript.
Acknowledgements
This work has been partly supported by NIH R56 Grant 1R56DK089493-01 awarded to Drs. Jyoti N. Sengupta and Banani Banerjee. A part of this work has also been supported by Digestive Disease Center grant of Medical College of Wisconsin awarded to Dr. Jyoti N. Sengupta.
References (64)
- et al.
The 5-HT1A receptor: signaling, desensitization, and gene transcription
Neuropsychopharmacology
(1996) - et al.
The actions of 5-HT1 agonists and antagonists on nociceptive processing in the rat spinal cord: results from behavioural and electrophysiological studies
Brain Res
(1994) - et al.
Serotonin receptor subtypes involved in the spinal antinociceptive effect of 5-HT in rats
Pain
(2000) - et al.
Activation of serotonin1A receptors inhibits midbrain periaqueductal gray neurons of the rat
Brain Res
(1993) - et al.
Spinal 5-HT1A receptors differentially influence nociceptive processing according to the nature of the noxious stimulus in rats: effect of WAY-100635 on the antinociceptive activities of paracetamol, venlafaxine and 5-HT
Pain
(2005) - et al.
Receptor localization in the mammalian dorsal horn and primary afferent neurons
Brain Res Rev
(1997) - et al.
Analgesic effects of serotonin and receptor-selective serotonin agonists in the rat spinal cord
Gen Pharmacol
(1991) - et al.
Serotonin contributes to the spinal antinociceptive effects of morphine
Pharmacol Biochem Behav
(1991) - et al.
Autoradiographic evidence of serotonin1 binding sites on primary afferent fibres in the dorsal horn of the rat spinal cord
Neurosci Lett
(1987) - et al.
Different role of 5-HT1A and 5-HT2 receptors in spinal cord in the control of nociceptive responsiveness
Neuropharmacology
(1991)
Heterogeneous effects of serotonin in the dorsal horn of rat: the involvement of 5-HT1 receptor subtypes
Brain Res
A 5-HT1-type receptor mediates the antinociceptive effect of nucleus raphe magnus stimulation in the rat
Brain Res
5-HT1A agonists induce central cholinergic antinociception
Pharmacol Biochem Behav
Antinociceptive effects of the novel anxiolytic buspirone in three pain tests in rats
Pain
Putative mechanisms of buspirone-induced antinociception in the rat
Pain
The effect of 5-HT1A receptor stimulation on nociceptive dorsal horn neurones in rats
Eur J Pharmacol
Involvement of glutamate neurotransmission and N-methyl-d-aspartate receptor in the activation of midbrain dopamine neurons by 5-HT1A receptor agonists: an electrophysiological study in the rat
Neuroscience
Identification of 5-hydroxytryptamine binding site subtypes in rat spinal cord
Brain Res
Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A−/−, 5-HT1B−/−, 5-HT2A−/−, 5-HT3A−/− and 5-HTT−/− knock-out male mice
Pain
Synergistic mu-opioid and 5-HT1A presynaptic inhibition of GABA release in rat periaqueductal gray neurons
Neuropharmacology
Role of presynaptic 5-HT1A and 5-HT3 receptors in modulation of synaptic GABA transmission in dissociated rat basolateral amygdala neurons
Life Sci
Autoradiographic mapping of serotonin 5-HT1A, 5-HT1D, 5-HT2A and 5-HT3 receptors in the aged human spinal cord
J Chem Neuroanat
Serotonin inhibits GABA synaptic transmission in presympathetic paraventricular nucleus neurons
Neurosci Lett
Autoradiographic mapping of 5-HT1, 5-HT1A, 5-HT1B and 5-HT2 receptors in the rat spinal cord
Brain Res
Redistribution of transmitter amino acids in rat hippocampus and cerebellum during seizures induced by l-allylglycine and bicuculline: an immunocytochemical study with antisera against conjugated GABA, glutamate and aspartate
Neuroscience
Antinociceptive effects of melatonin in a rat model of post-inflammatory visceral hyperalgesia: a centrally mediated process
Pain
Attenuation of opioid induced antinociception by 5-HT1A partial agonists in the rat
Neuropharmacology
Altered visceral sensation in response to somatic pain in the rat
Gastroenterology
Selective serotonin1A/1B agonists differentially affect spinal nociceptive reflexes
Neuropharmacology
Dual effect of serotonin on formalin-induced nociception in the rat spinal cord
Neurosci Res
Modulation by serotonin of the neurons in rat nucleus raphe magnus in vitro
Neuroscience
5-Hydroxytryptamine receptor subtypes: molecular, biochemical and physiological characterization
Trends Neurosci
Cited by (10)
The Buspirone-dependent Abdominal Pain Transmission Within the Nucleus Tractus Solitarius in the Rat
2021, NeuroscienceCitation Excerpt :It is assumed the central abnormalities of serotoninergic transmission within the brain-gut axis are the main cause of abdominal pain in IBS patients (Kim and Camilleri, 2000; Bueno et al., 2007; Azpiroz et al., 2007). The 5-HT1a receptor (5-HT1aR) plays an important role in the central pain control mechanism (Mico et al., 2006; Mickle et al., 2012). The 5-HT1a receptors are distributed broadly in the CNS, found in the soma, dendrites, and the cell body.
Activation of 5-HT <inf>2C</inf> (but not 5-HT <inf>1A</inf> ) receptors in the amygdala enhances fear-induced antinociception: Blockade with local 5-HT <inf>2C</inf> antagonist or systemic fluoxetine
2018, NeuropharmacologyCitation Excerpt :For instance, Canto-de-Souza and colleagues (1998) demonstrated the blockade of social-defeat analgesia through intra-dPAG injection of BAY-R 1531, a 5-HT1A full agonist, whereas local injection of the 5-HT1A antagonist, WAY-100135, enhanced this type of environmentally induced pain inhibition. This antagonist also blocked the increase in the viscero-motor response to colorectal distension induced by 8-OH-DPAT (Mickle et al., 2012). The pro-nociceptive property of 8-OH-DPAT and the antinociceptive effect of WAY-100135 have already been reported by Millan and colleagues (1995).
Central α-adrenoceptors contribute to mustard oil-induced central sensitization in the rat medullary dorsal horn
2013, NeuroscienceCitation Excerpt :Notably, an earlier study has reported that the effects of phentolamine are mediated by its direct blocking of presynaptic serotonin autoreceptors (Limberger et al., 1989). A recent visceral pain study has demonstrated that the activation of presynaptic serotonergic 5-HT(1A) receptors in spinal GABAergic neurons can restrict GABA release and thereby disinhibit the excitatory glutamatergic neurons, producing a pronociceptive effect (Mickle et al., 2012). Therefore, the phentolamine-induced attenuation of MDH central sensitization can be explained by its blocking effect on presynaptic 5-HT receptors of GABAergic neurons; these mechanisms may also have been involved in guanethidine’s effect in the present study.
Opposing effects of 5-HT1A receptor agonist buspirone on supraspinal abdominal pain transmission in normal and visceral hypersensitive rats
2023, Journal of Neuroscience ResearchThe central effects of buspirone on abdominal pain in rats
2018, Neurogastroenterology and Motility