Serotonergic modulation of nociceptive circuits in spinal cord dorsal horn

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

Transient, activity dependent inhibition of transmitter release from low threshold afferents mediated by GABA A receptors in spinal cord lamina III/IV

Background Presynaptic GABA A receptors (GABA A Rs) located on central terminals of low threshold afferent fibers are thought to be involved in the processing of touch and possibly in the generation of tactile allodynia in chronic pain. These GABA A Rs mediate primary afferent depolarization (PAD) and modulate transmitter release. The objective of this study was to expand our understanding of the presynaptic inhibitory action of GABA released onto primary afferent central terminals following afferent stimulation. Results We recorded evoked postsynaptic excitatory responses (eEPSCs and eEPSPs) from lamina III/IV neurons in spinal cord slices from juvenile rats (P17–P23, either sex), while stimulating dorsal roots. We investigated time and activity dependent changes in glutamate release from low threshold A fibers and the impact of these changes on excitatory drive. Blockade of GABA A Rs by gabazine potentiated the second eEPSC during a train of four afferent stimuli in a large subset of synapses. This resulted in a corresponding increase of action potential firing after the second stimulus. The potentiating effect of gabazine was due to inhibition of endogenously activated presynaptic GABA A Rs, because it was not prevented by the blockade of postsynaptic GABA A Rs through intracellular perfusion of CsF. Exogenous activation of presynaptic GABA A Rs by muscimol depressed evoked glutamate release at all synapses and increased paired pulse ratio (PPR). Conclusions These observations suggest that afferent driven release of GABA onto low threshold afferent terminals is most effective following the first action potential in a train and serves to suppress the initial strong excitatory drive onto dorsal horn circuitry

GABAB receptors-mediated tonic inhibition of glutamate release from A\u3b2 fibers in rat laminae III/IV of the spinal cord dorsal horn.

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 A\u3b2 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 A\u3b2 fiber stimulation and recorded from lamina III/IV neurons in spinal cord slices, were strongly depressed by application of baclofen (0.1-2.5\u2009\ub5M), 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 A\u3b2 fibers. These results suggest that GABABRs tonically inhibit glutamate release from A\u3b2 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 neuron

Mechanisms of Peripheral and Central Pain Sensitization: Focus on Ocular Pain

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

Osteoporosis in Light of a New Mechanism Theory of Delayed Onset Muscle Soreness and Non-Contact Anterior Cruciate Ligament Injury

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

Influence of Attention Control on Implicit and Explicit Emotion Processing of Face and Body: Evidence From Flanker and Same-or-Different Paradigms

Many existing findings indicate that processing of emotional information is pre-attentive, largely immune from attentional control. Nevertheless, inconsistent evidence on the interference of emotional cues on cognitive processing suggests that this influence may be a highly conditional phenomenon. The aim of the present study was twofold: (1) to examine the modulation of attention control on emotion processing using facial expressions (2) explore the very same effect for emotional body expressions. In Experiment 1, participants performed a Flanker task in which they had to indicate either the emotion (happy/fearful) or the gender of the target stimulus while ignoring the distracting stimuli at the side. We found evidence for intrusion of the emotional dimension of a stimulus in both the emotion and gender discrimination performance, thus when either task-relevant or task-irrelevant. To further explore the influence of attention control mechanisms, in Experiment 2 participants performed a same-or-different judgment task in which they were asked to pay attention to both the central and lateral stimuli and indicated whether the central stimulus matched the lateral for emotion or gender. Results showed that emotional features exerted an influence at an implicit level (i.e., during gender judgments) for bodies only. Gender features did not affect emotional processing in either experiments. To rule out the possibility that this effect was driven by postural rather than emotional features of fearful vs. happy stimuli, a control experiment was conducted. In Experiment 3, bodies with an opening/up-ward or closing/down-ward posture but with no emotional valence were presented. Results revealed that the body posture did not influence gender discrimination. Findings suggest that the emotional valence of a face or body stimulus can overpass attention filtering mechanisms, independently from the level of attentional modulation (Experiment 1). However, broadening the focus of attention to include the lateral stimuli led emotional information to intrude on the main task, exerting an implicit, bottom–up influence on gender processing, only when conveyed by bodies (Experiment 2). Results point to different mechanisms for the implicit processing of face and body emotional expressions, with the latter likely having role on action preparation processes

5-HT7 Receptors Regulate Excitatory-Inhibitory Balance in Mouse Spinal Cord Dorsal Horn

Serotonergic receptors of the 5-HT7 type (5-HT7Rs) 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-HT7Rs, although an analgesic effect seems to be prevalent. In the spinal cord dorsal horn, the mechanisms involved in 5-HT7R-mediated synaptic modulation are still poorly understood, especially those regarding the control of synaptic inhibition. The present study investigated the modulation exerted by 5-HT7Rs 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-HT7 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-HT1A antagonist WAY-100635, while the 5-HT7 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-HT7R 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-HT7Rs 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

Body Processing in Children and Adolescents with Traumatic Brain Injury: An Exploratory Study

Dysfunctions in body processing have been documented in adults with brain damage, while limited information is available for children. This study aimed to investigate body processing in children and adolescents with traumatic brain injury (TBI) (N = 33), compared to peers with typical development. Two well-known computerized body-representation paradigms, namely Visual Body Recognition and Visuo-spatial Imagery, were administered. Through the first paradigm, the body inversion and composite illusion effects were tested with a matching to sample task as measures of configural and holistic processing of others’ bodies, respectively. The second paradigm investigated with a laterality judgement task the ability to perform first-person and object-based mental spatial transformations of own body and external objects, respectively. Body stimuli did not convey any emotional contents or symbolic meanings. Patients with TBI had difficulties with mental transformations of both body and object stimuli, displaying deficits in motor and visual imagery abilities, not limited to body processing. Therefore, cognitive rehabilitation of body processing in TBI might benefit from the inclusion of both general training on visuo-spatial abilities and specific exercises aimed at boosting visual body perception and motor imagery