Biology subjects

Chirila, A. M.

Publications and source records attributed to Chirila, A. M..

4 recordsLinked to original sources

bioRxiv2026

Targeting Gi/o-coupled GPCRs to inhibit nociceptors: insights from the serotonin receptor Htr1b and triptans

Pain perception is initiated upon activation of nociceptors of the dorsal root ganglia (DRG) and trigeminal ganglia. We identified G protein-coupled receptors (GPCRs) expressed in CGRP+ mouse and human DRG neurons and found that agonists of several identified Gi/o-coupled and orphan GPCRs attenuated neuronal excitability. Experiments focusing on the Gi/o-coupled serotonin receptor Htr1b, which is expressed in mouse and human CGRP+ DRG neurons, revealed that Htr1b/1d agonists, the triptans sumatriptan and zolmitriptan, attenuated CGRP+ neuron excitability in vitro and exhibited analgesia across several pain models, including neuropathic pain. Conditional genetic deletion experiments showed that triptan-induced analgesia is mediated by Htr1b expressed in A-fiber mechanonociceptors. Also, triptan-associated adverse effects are partially mediated by Htr1b-independent targets. Further testing identified the GPCR Gpr19 as an additional promising target for treating pain. These findings establish a preclinical screening platform for identifying novel analgesics and reveal nociceptor GPCRs that may be targeted to treat pain.

neuroscience↗

bioRxiv2023

Nerve injury disrupts temporal processing in the spinal cord dorsal horn through alterations in PV+ interneurons

How mechanical allodynia following nerve injury is encoded in patterns of neural activity in the spinal cord dorsal horn (DH) is not known. We addressed this using the spared nerve injury model of neuropathic pain and in vivo electrophysiological recordings. Surprisingly, despite dramatic behavioral over-reactivity to mechanical stimuli following nerve injury, an overall increase in sensitivity or reactivity of DH neurons was not observed. We did, however, observe a marked decrease in correlated neural firing patterns, including the synchrony of mechanical stimulus-evoked firing, across the DH. Alterations in DH temporal firing patterns were recapitulated by silencing DH parvalbumin+ (PV+) inhibitory interneurons, previously implicated in mechanical allodynia, as were allodynic pain-like behaviors in mice. These findings reveal decorrelated DH network activity, driven by alterations in PV+ interneurons, as a prominent feature of neuropathic pain, and suggest that restoration of proper temporal activity is a potential treatment for chronic neuropathic pain.

neuroscience↗

bioRxiv2022

Mechanoreceptor signal convergence and transformation in the dorsal horn flexibly shape a diversity of outputs to the brain

The encoding of touch in the spinal cord dorsal horn (DH) and its influence on tactile representations in the brain are poorly understood. Using a range of mechanical stimuli applied to the skin, large scale in vivo electrophysiological recordings, and genetic manipulations, here we show that neurons in the mouse spinal cord DH receive convergent inputs from both low- and high-threshold mechanoreceptor subtypes and exhibit one of six functionally distinct mechanical response profiles. Genetic disruption of DH feedforward or feedback inhibitory motifs, comprised of interneurons with distinct mechanical response profiles, revealed an extensively interconnected DH network that enables dynamic, flexible tuning of postsynaptic dorsal column (PSDC) output neurons and dictates how neurons in primary somatosensory cortex respond to touch. Thus, mechanoreceptor subtype convergence and nonlinear transformations at the earliest stage of the somatosensory hierarchy shape how touch of the skin is represented in the brain.

neuroscience↗

bioRxiv2019

NMDA receptor activation induces long-term potentiation of glycine synapses

Of the fast ionotropic synapses, glycinergic synapses are the least well understood, but are vital for the maintenance of inhibitory signaling in the brain and spinal cord. Glycinergic signaling comprises half of the inhibitory signaling in the spinal cord, and glycinergic synapses are likely to regulate local nociceptive processing as well as the transmission to the brain of peripheral nociceptive information. Here we have investigated the rapid and prolonged potentiation of glycinergic synapses in the superficial dorsal horn of young male and female mice after brief activation of NMDA receptors (NMDARs). Glycinergic inhibitory postsynaptic currents (IPSCs) evoked with lamina II-III stimulation in identified GABAergic neurons in lamina II were potentiated by bath-applied Zn2+ and were depressed by the prostaglandin PGE2, consistent with the presence of both GlyR1- and GlyR3-containing receptors. NMDA application rapidly potentiated synaptic glycinergic currents. Whole-cell currents evoked by exogenous glycine were also rapidly potentiated by NMDA, indicating that the potentiation results from altered numbers or conductance of postsynaptic glycine receptors. Repetitive depolarization alone of the postsynaptic GABAergic neuron also potentiated glycinergic synapses, and intracellular EGTA prevented both NMDA-induced and depolarization-induced potentiation of glycinergic IPSCs. Driving trpv1 lineage afferents optogenetically also triggered NMDAR-dependent potentiation of glycinergic synapses. Our results suggest that during peripheral injury or inflammation, nociceptor firing during injury is likely to potentiate glycinergic synapses on GABAergic neurons. This disinhibition mechanism may be engaged rapidly, altering dorsal horn circuitry to promote the transmission of nociceptive information to the brain.\n\nSignificanceOf the fast ionotropic synapses, glycinergic synapses are the least well understood, yet glycinergic synapses comprise half of the inhibition in the spinal cord, and are likely to regulate local nociceptive processing as well as the transmission to the brain of peripheral nociceptive information. Here we report that bath applied NMDA, repetitive postsynaptic depolarization, or optogenetic activation of primary nociceptor afferents all produce LTP at superficial dorsal horn synapses. During peripheral injury or inflammation, nociceptor firing is likely to engage this mechanism in inhibitory neurons, rapidly altering dorsal horn circuitry to promote the transmission of nociceptive information to the brain.

neuroscience↗