-
European Journal of Pharmacology Mar 2023and purpose: Phenazopyridine (PAP) is an over-the-counter drug widely used to provide symptomatic relief of bladder pain in conditions such as cystitis or bladder pain...
BACKGROUND
and purpose: Phenazopyridine (PAP) is an over-the-counter drug widely used to provide symptomatic relief of bladder pain in conditions such as cystitis or bladder pain syndrome (BPS). Whereas the analgesic effect of PAP has been attributed to a local effect on the mucosa of the lower urinary tract (LUT), the molecular targets of PAP remain unknown. We investigated the effect of PAP on pain-related Transient Receptor Potential (TRP) channels expressed in sensory neurons that innervate the bladder wall.
EXPERIMENTAL APPROACH
The effects of PAP on the relevant TRP channels (TRPV1, TRPA1, TRPM8, TRPM3) expressed in HEK293 or CHO cells was investigated using Fura-2-based calcium measurements and whole-cell patch-clamp recordings. Activity of PAP on TRPM8 was further analysed using Fura-2-based calcium imaging on sensory neurons isolated from lumbosacral dorsal root ganglia (DRG) of mice.
KEY RESULTS
PAP rapidly and reversibly inhibits responses of TRPM8 expressed in HEK293 cells to cold and menthol, with IC values between 2 and 10 μM. It acts by shifting the voltage dependence of channel activation towards positive potentials, opposite to the effect of menthol. PAP also inhibits TRPM8-mediated, menthol-evoked calcium responses in lumbosacral DRG neurons. At a concentration of 10 μM, PAP did not significantly affect TRPA1, TRPV1, or TRPM3.
CONCLUSION AND IMPLICATIONS
PAP inhibits TRPM8 in a concentration range consistent with PAP levels in the urine of treated patients. Since TRPM8 is expressed in bladder afferent neurons and upregulated in patients with painful bladder disorders, TRPM8 inhibition may underlie the analgesic activity of PAP.
Topics: Animals; Cricetinae; Humans; Mice; Calcium; Cricetulus; Fura-2; Ganglia, Spinal; HEK293 Cells; Menthol; Pain; Phenazopyridine; Sensory Receptor Cells; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPM Cation Channels; Urinary Bladder
PubMed: 36657655
DOI: 10.1016/j.ejphar.2023.175512 -
Developmental Dynamics : An Official... Jan 2023Sensory neurons of the head are the ones that transmit the information about the external world to our brain for its processing. Axons from cranial sensory neurons sense... (Review)
Review
Sensory neurons of the head are the ones that transmit the information about the external world to our brain for its processing. Axons from cranial sensory neurons sense different chemoattractant and chemorepulsive molecules during the journey and in the target tissue to establish the precise innervation with brain neurons and/or receptor cells. Here, we aim to unify and summarize the available information regarding molecular mechanisms guiding the different afferent sensory axons of the head. By putting the information together, we find the use of similar guidance cues in different sensory systems but in distinct combinations. In vertebrates, the number of genes in each family of guidance cues has suffered a great expansion in the genome, providing redundancy, and robustness. We also discuss recently published data involving the role of glia and mechanical forces in shaping the axon paths. Finally, we highlight the remaining questions to be addressed in the field.
Topics: Animals; Axon Guidance; Axons; Sensory Receptor Cells; Neuroglia; Sense Organs
PubMed: 35972036
DOI: 10.1002/dvdy.523 -
The Journal of Neuroscience : the... Apr 2022Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate...
Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate for pain referral in primary headache syndromes. Lamina I neurons are central to this mechanism, as they relay convergent nociceptive input to supraspinal pain centers. Unfortunately, little is known about the interactions between trigeminal and cervical afferents supplying Lamina I neurons. Here, we used rats of both sexes to show that cervical and trigeminal afferents interact via presynaptic inhibition, where monosynaptic inputs to Lamina I neurons undergo unidirectional as well as reciprocal presynaptic control. This means that afferent-driven presynaptic inhibition shapes the way trigeminal and cervical Aδ-fiber and C-fiber input reaches Lamina I projection neurons (PNs) and local-circuit neurons (LCNs). We propose that this inhibition provides a feedforward control of excitatory drive to Lamina I neurons that regulates their convergent and cervical-specific or trigeminal-specific processing modes. As a consequence, disruption of the trigeminal and cervical afferent-driven presynaptic inhibition may contribute to development of primary headache syndromes. Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate for pain referral in primary headache syndromes. Lamina I neurons are central to this mechanism as they relay convergent nociceptive input to supraspinal pain centers. Here, we show that cervical and trigeminal afferents interact via presynaptic inhibition, where inputs to Lamina I neurons undergo unidirectional as well as reciprocal control. The afferent-driven presynaptic inhibition shapes the trigeminocervical Aδ-fiber and C-fiber input to Lamina I neurons. This inhibition provides control of excitatory drive to Lamina I neurons that regulates their convergent and cervical-specific or trigeminal-specific processing modes. Disruption of this control may contribute to development of primary headache syndromes.
Topics: Animals; Female; Headache Disorders; Male; Nerve Fibers, Unmyelinated; Neurons, Afferent; Nociception; Pain; Rats; Spinal Cord Dorsal Horn
PubMed: 35318285
DOI: 10.1523/JNEUROSCI.0025-22.2022 -
Journal of the Association For Research... Jun 2022Vestibular evoked myogenic potentials (VEMPs) are routinely used to test otolith function, but which specific vestibular afferent neurons and central circuits are...
Vestibular evoked myogenic potentials (VEMPs) are routinely used to test otolith function, but which specific vestibular afferent neurons and central circuits are activated by auditory frequency VEMP stimuli remains unclear. To examine this question, we analyzed the sensitivity of individual vestibular afferents in adult Sprague-Dawley rats to tone bursts delivered at 9 frequencies (125-4000 Hz) and 3 intensity levels (60, 70, 80 dB SL re: acoustic brainstem response (ABR) threshold). Afferent neuron tone sensitivity was quantified by the cumulative probability of evoking a spike (CPE). Based on a threshold CPE of 0.1, acoustic stimuli in the present study evoked responses in 78.2 % (390/499) of otolith afferent neurons vs. 48.4 % (431/891) of canal afferent neurons. Organ-specific vestibular inputs to the central nervous system in response to tone bursts differ based on intensity and frequency content of the stimulus. At frequencies below 500 Hz, tone bursts primarily activated both otolith afferents, even at the highest intensity tested (80 dB SL re ABR threshold). At 1500 Hz, however, tone bursts activated the canal and otolith afferents at the moderate and high intensities tested (70, 80 dB SL), but activated only otolith afferents at the low intensity tested (60 dB SL). Within an end organ, diversity of sensitivity between individual afferent neurons correlated with spontaneous discharge rate and regularity. Examination of inner ear fluid mechanics in silico suggests that the frequency response and preferential activation of the otolith organs likely arise from inner ear fluid motion trapped near the oval and round windows. These results provide insight into understanding the mechanisms of sound activation of the vestibular system and developing novel discriminative VEMP testing protocols and interpretative guidelines in humans.
Topics: Acoustic Stimulation; Acoustics; Animals; Otolithic Membrane; Rats; Rats, Sprague-Dawley; Vestibular Evoked Myogenic Potentials
PubMed: 35378621
DOI: 10.1007/s10162-022-00839-1 -
International Journal of Molecular... Jan 2021Sensory primary afferent fibers, conveying touch, pain, itch, and proprioception, synapse onto spinal cord dorsal horn neurons. Primary afferent central terminals... (Review)
Review
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.
Topics: Animals; Astrocytes; GABA Antagonists; GABAergic Neurons; Nerve Fibers; Neurons, Afferent; Pain; Receptors, GABA; Spinal Cord Dorsal Horn; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 33401784
DOI: 10.3390/ijms22010414 -
Molecular Pain 2021Aβ-afferents in maxillary or V2 trigeminal ganglion (TG) neurons are somatosensory neurons that may be involved in both non-nociceptive and nociceptive functions in...
Aβ-afferents in maxillary or V2 trigeminal ganglion (TG) neurons are somatosensory neurons that may be involved in both non-nociceptive and nociceptive functions in orofacial regions. However, electrophysiological properties of these V2 trigeminal Aβ-afferent neurons have not been well characterized so far. Here, we used rat trigeminal nerve preparations and applied patch-clamp recordings to large-sized V2 TG neurons to characterize their electrophysiological properties. All the cells recorded had afferent conduction velocities in the range of Aβ-afferent conduction speeds. However, these V2 trigeminal Aβ-afferent neurons displayed different action potential (AP) properties. APs showed fast kinetics in some cells but slow kinetics with shoulders in repolarization phases in other cells. Based on the derivatives of voltages in AP repolarization with time (dV/dt), we classified V2 trigeminal Aβ-afferent neurons into four types: type I, type II, type IIIa and type IIIb. Type I V2 trigeminal Aβ-afferent neurons had the largest dV/dt of repolarization, the fastest AP conduction velocities, the shortest AP and afterhyperpolarization (AHP) durations, and the highest AP success rates. In contrast, type IIIb V2 trigeminal Aβ-afferent neurons had the smallest dV/dt of AP repolarization, the slowest AP conduction velocities, the longest AP and AHP durations, and the lowest AP success rates. The type IIIb cells also had significantly lower voltage-activated K currents. For type II and type IIIa V2 trigeminal Aβ-afferent neurons, AP parameters were in the range between those of type I and type IIIb V2 trigeminal Aβ-afferent neurons. Our electrophysiological classification of V2 trigeminal Aβ-afferent neurons may be useful in future to study their non-nociceptive and nociceptive functions in orofacial regions.
Topics: Action Potentials; Animals; Membrane Potentials; Neurons, Afferent; Rats; Rats, Sprague-Dawley; Trigeminal Ganglion
PubMed: 34056968
DOI: 10.1177/17448069211021271 -
ELife Jun 2022Animals can evolve dramatic sensory functions in response to environmental constraints, but little is known about the neural mechanisms underlying these changes. The...
Animals can evolve dramatic sensory functions in response to environmental constraints, but little is known about the neural mechanisms underlying these changes. The Mexican tetra, , is a leading model to study genetic, behavioral, and physiological evolution by comparing eyed surface populations and blind cave populations. We compared neurophysiological responses of posterior lateral line afferent neurons and motor neurons across populations to reveal how shifts in sensory function may shape behavioral diversity. These studies indicate differences in intrinsic afferent signaling and gain control across populations. Elevated endogenous afferent activity identified a lower response threshold in the lateral line of blind cavefish relative to surface fish leading to increased evoked potentials during hair cell deflection in cavefish. We next measured the effect of inhibitory corollary discharges from hindbrain efferent neurons onto afferents during locomotion. We discovered that three independently derived cavefish populations have evolved persistent afferent activity during locomotion, suggesting for the first time that partial loss of function in the efferent system can be an evolutionary mechanism for neural adaptation of a vertebrate sensory system.
Topics: Animals; Biological Evolution; Caves; Characidae; Lateral Line System; Locomotion
PubMed: 35708234
DOI: 10.7554/eLife.77387 -
Journal of Applied Physiology... Aug 2020Hyperoxia reduces the ventilatory response to hypercapnia by suppressing carotid body (CB) activation. This effect may contribute to CO retention during underwater...
Hyperoxia reduces the ventilatory response to hypercapnia by suppressing carotid body (CB) activation. This effect may contribute to CO retention during underwater diving due to the high arterial O content associated with hyperbaria. We tested the hypothesis that CB chemosensitivity to hypercapnia and hypoxia is attenuated during hyperbaria. Ten subjects completed two, 4-h dry dives at 1.6 atmosphere absolute (ATA) breathing either 21% O (Air) or 100% O (100% O). CB chemosensitivity was assessed using brief hypercapnic ventilatory response ([Formula: see text]) and hypoxic ventilatory response ([Formula: see text]) tests predive, 75 and 155 min into the dives, and 15 and 55 min postdive. End-tidal CO pressure increased during the dive at 75 and 155 min [Air: +9 (SD 4) mmHg and +8 (SD 4) mmHg versus 100% O: +6 (SD 4) mmHg and +5 (SD 3) mmHg; all < 0.01] and was higher while breathing Air ( < 0.01). [Formula: see text] was unchanged during the dive ( = 0.73) and was not different between conditions ( = 0.47). However, [Formula: see text] was attenuated from predive during the dive at 155 min breathing Air [-0.035 (SD 0.037) L·min·mmHg; = 0.02] and at both time points while breathing 100% O [-0.035 (SD 0.052) L·min·mmHg and -0.034 (SD 0.064) L·min·mmHg; = 0.02 and = 0.02, respectively]. These data indicate that the CB chemoreceptors do not appear to contribute to CO retention in hyperbaria. We demonstrate that carotid body chemosensitivity to brief exposures of hypercapnia was unchanged during a 4-h dive in a dry hyperbaric chamber at 1.6 ATA regardless of breathing gas condition [i.e., air (21% O) versus 100% oxygen]. Therefore, it appears that an attenuation of carotid body chemosensitivity to hypercapnia does not contribute to CO retention in hyperbaria.
Topics: Atmosphere; Carbon Dioxide; Carotid Body; Chemoreceptor Cells; Humans; Hypercapnia; Hypoxia; Oxygen
PubMed: 32584669
DOI: 10.1152/japplphysiol.00275.2020 -
American Journal of Physiology.... Aug 2021Bile acid reflux in the esophagus plays a role in the pathogenesis of certain esophageal disorders, where it can induce esophageal pain and heartburn. The present study...
Bile acid reflux in the esophagus plays a role in the pathogenesis of certain esophageal disorders, where it can induce esophageal pain and heartburn. The present study aimed to determine whether bile acid, deoxycholic acid (DCA), directly activates and sensitizes esophageal vagal nociceptive afferent C-fiber subtypes. DCA-elicited effects on vagal nodose and jugular neurons were studied by calcium imaging. Its effects on esophageal-labeled nodose and jugular neurons were then determined by patch-clamp recording. At nodose and jugular C-fiber nerve endings in the esophagus, DCA-evoked action potentials (APs) were compared by extracellular single-unit recordings in ex vivo esophageal-vagal preparations. DCA application induced calcium influxes in nodose and jugular neurons and elicited inward currents in esophageal-labeled nodose and jugular neurons. In the presence of DCA, the current densities elicited by capsaicin were enhanced in those labeled neurons. Consistently, DCA perfusion at nerve terminals in the esophagus evoked APs in about 50% of esophageal nodose and jugular C-fibers. In DCA-sensitive C-fibers, DCA perfusion also sensitized the fibers such that the subsequent response to capsaicin was amplified. Collectively, these results provide new evidence that DCA directly activates and sensitizes nociceptive nodose and jugular C-fibers in the esophagus. Such activation and sensitization effects may contribute to bile acid-induced esophageal nociceptive symptoms that are refractory to proton-pump inhibitor therapy. Bile acid reflux in the esophagus can induce pain and heartburn in certain esophageal disorders, but the underlying neuronal mechanism is still unclear. The present study demonstrated that bile acid, deoxycholic acid (DCA), directly activates esophageal vagal afferent nodose and jugular nociceptive C-fibers and sensitizes their response to capsaicin. Such effects may contribute to bile acid-induced esophageal nociceptive symptoms that refractory to proton-pump inhibitors (PPIs) therapy.
Topics: Action Potentials; Animals; Calcium Signaling; Cells, Cultured; Cholagogues and Choleretics; Deoxycholic Acid; Esophagus; Guinea Pigs; Nerve Fibers, Unmyelinated; Nociceptors; Vagus Nerve
PubMed: 34160291
DOI: 10.1152/ajpgi.00187.2021 -
Journal of Neurophysiology Nov 2021has a lateral line mechanosensory system throughout its full life cycle, and a previous study on prefeeding stage tadpoles revealed that it may play a role in motor...
has a lateral line mechanosensory system throughout its full life cycle, and a previous study on prefeeding stage tadpoles revealed that it may play a role in motor responses to both water suction and water jets. Here, we investigated the physiology of the anterior lateral line system in newly hatched tadpoles and the motor outputs induced by its activation in response to brief suction stimuli. High-speed videoing showed tadpoles tended to turn and swim away when strong suction was applied close to the head. The lateral line neuromasts were revealed by using DASPEI staining, and their inactivation with neomycin eliminated tadpole motor responses to suction. In immobilized preparations, suction or electrically stimulating the anterior lateral line nerve reliably initiated swimming but the motor nerve discharges implicating turning was observed only occasionally. The same stimulation applied during ongoing fictive swimming produced a halting response. The anterior lateral line nerve showed spontaneous afferent discharges at rest and increased activity during stimulation. Efferent activities were only recorded during tadpole fictive swimming and were largely synchronous with the ipsilateral motor nerve discharges. Finally, calcium imaging identified neurons with fluorescence increase time-locked with suction stimulation in the hindbrain and midbrain. A cluster of neurons at the entry point of the anterior lateral line nerve in the dorsolateral hindbrain had the shortest latency in their responses, supporting their potential sensory interneuron identity. Future studies need to reveal how the lateral line sensory information is processed by the central circuit to determine tadpole motor behavior. We studied tadpole motor responses to anterior lateral line stimulation using high-speed videos, electrophysiology and calcium imaging. Activating the lateral line reliably started swimming. At high stimulation intensities, turning was observed behaviorally but suitable motor nerve discharges were seen only occasionally in immobilized tadpoles. Suction applied during swimming produced a halting response. We analyzed afferent and efferent activities of the tadpole anterior lateral line nerve and located sensory interneurons using calcium imaging.
Topics: Animals; Behavior, Animal; Interneurons; Larva; Lateral Line System; Motor Activity; Neurons, Afferent; Neurons, Efferent; Rhombencephalon; Xenopus laevis
PubMed: 34705593
DOI: 10.1152/jn.00618.2020