Background: Despite the extensive number of studies performed in the last 50 years, aimed at describing the role of serotonin and its receptors in pain modulation at the spinal cord level, several ...aspects are still not entirely understood. The interpretation of these results is often complicated by the use of different pain models and animal species, together with the lack of highly selective agonists and antagonists binding to serotonin receptors.
Method: In this review, a search has been conducted on studies investigating the modulatory action exerted by serotonin on specific neurons and circuits in the spinal cord dorsal horn. Particular attention has been paid to studies employing electrophysiological techniques, both in vivo and in vitro.
Conclusion: The effects of serotonin on pain transmission in dorsal horn depend on several factors, including the type of receptors activated and the populations of neurons involved. Recently, studies performed by activating and/or recording from identified neurons have importantly contributed to the understanding of serotonergic modulation on dorsal horn circuits.
The biogenic amine serotonin modulates pain perception by activating several types of serotonergic receptors, including the 5-HT7 type. These receptors are widely expressed along the pain axis, both ...peripherally, on primary nociceptors, and centrally, in the spinal cord and the brain. The role of 5-HT7 receptors in modulating pain has been explored in vivo in different models of inflammatory and neuropathic pain. While most studies have reported an antinociceptive effect of 5-HT7 receptor activation, some authors have suggested a pronociceptive action. Differences in pain models, animal species and gender, receptor types, agonists, and route of administration could explain these discrepancies. In this mini-review, some of the main findings concerning the function of 5-HT7 receptors in the pain system have been presented. The expression patterns of the receptors at the different levels of the pain axis, along with the cellular mechanisms involved in their activity, have been described. Alterations in receptor expression and/or function in different pain models and the role of 5-HT7 receptors in controlling pain transmission have also been discussed. Finally, some of the future perspectives in this field have been outlined.
Sensory primary afferent fibers, conveying touch, pain, itch, and proprioception, synapse onto spinal cord dorsal horn neurons. Primary afferent central terminals express a wide variety of receptors ...that modulate glutamate and peptide release. Regulation of the amount and timing of neurotransmitter release critically affects the integration of postsynaptic responses and the coding of sensory information. The role of GABA (γ-aminobutyric acid) receptors expressed on afferent central terminals is particularly important in sensory processing, both in physiological conditions and in sensitized states induced by chronic pain. During the last decade, techniques of opto- and chemogenetic stimulation and neuronal selective labeling have provided interesting insights on this topic. This review focused on the recent advances about the modulatory effects of presynaptic GABAergic receptors in spinal cord dorsal horn and the neural circuits involved in these mechanisms.
Nociceptive primary afferents release glutamate, activating postsynaptic glutamate receptors on spinal cord
dorsal horn neurons. Glutamate receptors, both ionotropic and metabotropic, are also ...expressed on presynaptic terminals,
where they regulate neurotransmitter release. During the last two decades, a wide number of studies have characterized
the properties of presynaptic glutamatergic receptors, particularly those expressed on primary afferent fibers. This review
describes the subunit composition, distribution and function of presynaptic glutamate ionotropic (AMPA, NMDA,
kainate) and metabotropic receptors expressed in rodent spinal cord dorsal horn. The role of presynaptic receptors in
modulating nociceptive information in experimental models of acute and chronic pain will be also discussed.
Osteoporosis is a disorder, with a largely unknown pathomechanism, that is often marked as a “silent thief”, because it usually only becomes undisguised when fractures occur. This implies that the ...pathological damage occurs earlier than the sensation of pain. The current authors put forward a non-contact injury model in which the chronic overloading of an earlier autologously microinjured Piezo2 ion channel of the spinal proprioceptor terminals could lead the way to re-injury and earlier aging in a dose-limiting and threshold-driven way. As a result, the aging process could eventually lead the way to the metabolic imbalance of primary osteoporosis in a quad-phasic non-contact injury pathway. Furthermore, it is emphasised that delayed onset muscle soreness, non-contact anterior cruciate injury and osteoporosis could have the same initiating proprioceptive non-contact Piezo2 channelopathy, at different locations, however, with different environmental risk factors and a different genetic predisposition, therefore producing different outcomes longitudinally. The current injury model does not intend to challenge any running pathogenic theories or findings, but rather to highlight a principal injury mechanism.
Persistent ocular pain caused by corneal inflammation and/or nerve injury is accompanied by significant alterations along the pain axis. Both primary sensory neurons in the trigeminal nerves and ...secondary neurons in the spinal trigeminal nucleus are subjected to profound morphological and functional changes, leading to peripheral and central pain sensitization. Several studies using animal models of inflammatory and neuropathic ocular pain have provided insight about the mechanisms involved in these maladaptive changes. Recently, the advent of new techniques such as optogenetics or genetic neuronal labelling has allowed the investigation of identified circuits involved in nociception, both at the spinal and trigeminal level. In this review, we will describe some of the mechanisms that contribute to the perception of ocular pain at the periphery and at the spinal trigeminal nucleus. Recent advances in the discovery of molecular and cellular mechanisms contributing to peripheral and central pain sensitization of the trigeminal pathways will be also presented.
Serotonergic receptors of the 5-HT
7
type (5-HT
7
Rs) are widely expressed in the central nervous system (CNS), where they modulate several functions, such as pain. Behavioral experiments
in vivo
...have shown both anti- and pro-nociceptive actions of 5-HT
7
Rs, although an analgesic effect seems to be prevalent. In the spinal cord dorsal horn, the mechanisms involved in 5-HT
7
R-mediated synaptic modulation are still poorly understood, especially those regarding the control of synaptic inhibition. The present study investigated the modulation exerted by 5-HT
7
Rs on dorsal horn excitatory and inhibitory synaptic circuits, by performing patch-clamp recordings from lamina II neurons in mouse spinal cord slices. Our results show that applying the selective 5-HT
7
agonist LP-211 facilitates glutamatergic release by enhancing the frequency of spontaneous postsynaptic currents (sEPSCs) and increasing the peak amplitude of excitatory postsynaptic currents (EPSCs) evoked by dorsal root stimulation. The effects on sEPSCs were still observed in the presence of the 5-HT
1
A
antagonist WAY-100635, while the 5-HT
7
antagonist SB-269970 blocked them. LP-211 was also able to increase the release of gamma-aminobutyric acid (GABA) and glycine, as shown by the increase of spontaneous inhibitory currents (sIPSC) frequency and evoked inhibitory postsynaptic currents (IPSC) amplitude. LP-211 was proved to be more effective in potentiating synaptic inhibition as compared to excitation: consistently, 5-HT
7
R activation significantly enhanced the excitability of tonic firing neurons, mainly corresponding to inhibitory interneurons. Our data bring new insights into the mechanisms of synaptic modulation mediated by 5-HT
7
Rs in the dorsal horn. Stronger impact on synaptic inhibition supports the hypothesis that these receptors may play an anti-nociceptive role in the spinal cord of naïve animals.
Presynaptic GABAB receptors (GABABRs) are highly expressed in dorsal root ganglion neurons and spinal cord dorsal horn. GABABRs located in superficial dorsal horn play an important antinociceptive ...role, by acting at both pre- and postsynaptic sites. GABABRs expressed in deep dorsal horn could be involved in the processing of touch sensation and possibly in the generation of tactile allodynia in chronic pain. The objective of this study was to characterize the morphological and functional properties of GABABRs expressed on Aβ fibers projecting to lamina III/IV and to understand their role in modulating excitatory synaptic transmission. We performed high-resolution electron microscopic analysis, showing that GABAB2 subunit is expressed on 71.9% of terminals in rat lamina III-IV. These terminals were engaged in axodendritic synapses and, for the 46%, also expressed glutamate immunoreactivity. Monosynaptic excitatory postsynaptic currents, evoked by Aβ fiber stimulation and recorded from lamina III/IV neurons in spinal cord slices, were strongly depressed by application of baclofen (0.1–2.5 µM), acting as a presynaptic modulator. Application of the GABABR antagonist CGP 55845 caused, in a subpopulation of neurons, the potentiation of the first of two excitatory postsynaptic currents recorded with the paired-pulse protocol, showing that GABABRs are endogenously activated. A decrease in the paired-pulse ratio accompanied the effect of CGP 55845, implying the involvement of presynaptic GABABRs. CGP 55845 facilitated only the first excitatory postsynaptic current also during a train of four consecutive stimuli applied to Aβ fibers. These results suggest that GABABRs tonically inhibit glutamate release from Aβ fibers at a subset of synapses in deep dorsal horn. This modulation specifically affects only the early phase of synaptic excitation in lamina III-IV neurons.
Abstract
Touch and itch sensations are crucial for evoking defensive and emotional responses, and light tactile touch may induce unpleasant itch sensations (mechanical itch or alloknesis). The neural ...substrate for touch-to-itch conversion in the spinal cord remains elusive. We report that spinal interneurons expressing
Tachykinin 2-Cre
(
Tac2
Cre
) receive direct Aβ low threshold mechanoreceptor (LTMR) input and form monosynaptic connections with GRPR neurons. Ablation or inhibition markedly reduces mechanical but not acute chemical itch nor noxious touch information. Chemogenetic inhibition of
Tac2
Cre
neurons also displays pronounced deficit in chronic dry skin itch, a type of chemical itch in mice. Consistently, ablation of gastrin-releasing peptide receptor (GRPR) neurons, which are essential for transmitting chemical itch, also abolishes mechanical itch. Together, these results suggest that innocuous touch and chemical itch information converge on GRPR neurons and thus map an exquisite spinal circuitry hard-wired for converting innocuous touch to irritating itch.
Sensory information transmitted to the spinal cord dorsal horn is modulated by a complex network of excitatory and inhibitory interneurons. The two main inhibitory transmitters, GABA and glycine, ...control the flow of sensory information mainly by regulating the excitability of dorsal horn neurons. A presynaptic action of GABA has also been proposed as an important modulatory mechanism of transmitter release from sensory primary afferent terminals. By inhibiting the release of glutamate from primary afferent terminals, activation of presynaptic GABA receptors could play an important role in nociceptive and tactile sensory coding, while changes in their expression or function could be involved in pathological pain conditions, such as allodynia.
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