scholarly journals In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans

2012 ◽  
Vol 107 (1) ◽  
pp. 357-363 ◽  
Author(s):  
C. Ma ◽  
H. Nie ◽  
Q. Gu ◽  
P. Sikand ◽  
R. H. LaMotte
Keyword(s):  
Time Course ◽  
Discharge Rate ◽  
Receptive Fields ◽  
Mechanical Stimuli ◽  
Nociceptive Neurons ◽  
Electrophysiological Recordings ◽  
The Mean ◽  
Chemical Stimuli ◽  
Temporal Profiles

Native cowhage spicules, and heat-inactivated spicules containing histamine or capsaicin, evoke similar sensations of itch and nociceptive sensations in humans. In ongoing studies of the peripheral neural mechanisms of chemical itch and pain in the mouse, extracellular electrophysiological recordings were obtained, in vivo, from the cell bodies of mechanosensitive nociceptive neurons in response to spicule stimuli delivered to their cutaneous receptive fields (RFs) on the distal hindlimb. A total of 43 mechanosensitive, cutaneous, nociceptive neurons with axonal conduction velocities in the C-fiber range (C-nociceptors) were classified as CM if responsive to noxious mechanical stimuli, such as pinch, or CMH if responsive to noxious mechanical and heat stimuli (51°C, 5 s). The tips of native cowhage spicules, or heat-inactivated spicules containing histamine or capsaicin, were applied to the RF. Heat-inactivated spicules containing no chemical produced only a transient response occurring during insertion. Of the 43 mechanosensitive nociceptors recorded, 20 of the 25 CMHs responded to capsaicin, and of these, 13 also responded to cowhage and/or histamine. In contrast, none of the 18 CMs responded to any of the chemical stimuli. The time course of the mean discharge rate of CMHs was similar in response to each type of spicule and generally similar, although reaching a peak earlier, to the temporal profiles of itch and nociceptive sensations evoked by the same stimuli in humans. These findings are consistent with the hypothesis that the itch and nociceptive sensations evoked by these punctuate chemical stimuli are mediated at least in part by the activity of mechanoheat-sensitive C-nociceptors. In contrast, activity in mechanosensitive C-nociceptors that do not respond to heat or to pruritic chemicals is hypothesized as contributing to pain but not to itch.

scholarly journals High-Throughput Controlled Mechanical Stimulation and Functional Imaging In Vivo

2017 ◽  
Author(s):  
Yongmin Cho ◽  
Daniel A. Porto ◽  
Hyundoo Hwang ◽  
Laura J. Grundy ◽  
William R. Schafer ◽  
...  
Keyword(s):  
Functional Imaging ◽  
Sensory Integration ◽  
Genetic Model ◽  
Receptive Fields ◽  
Model Systems ◽  
Mechanical Stimuli ◽  
C Elegans ◽  
Fluid Delivery ◽  
Chemical Stimuli

AbstractUnderstanding mechanosensation and other sensory behavior in genetic model systems such as C. elegans is relevant to many human diseases. These studies conventionally require immobilization by glue and manual delivery of stimuli, leading to low experimental throughput and high variability. Here we present a microfluidic platform that delivers precise mechanical stimuli robustly. The system can be easily used in conjunction with functional imaging and optical interrogation techniques, as well as other capabilities such as sorting or more sophisticated fluid delivery schemes. The platform is fully automated, thereby greatly enhancing the throughput and robustness of experiments. We show that behavior of the well-known gentle and harsh touch neurons and their receptive fields can be recapitulated in our system. Using calcium dynamics as a readout, we demonstrate the ability to perform a drug screen in vivo. Furthermore, using an integrated chip platform that can deliver both mechanical and chemical stimuli, we examine sensory integration in interneurons in response to multimodal sensory inputs. We envision that this system will be able to greatly accelerate the discovery of genes and molecules involved in mechanosensation and multimodal sensory behavior, as well as the discovery of therapeutics for related diseases.

The Comparative Pharmacodynamics of Remifentanil and Its Metabolite, GR90291, in a Rat Electroencephalographic Model 

1999 ◽  
Vol 90 (2) ◽  
pp. 535-544 ◽  
Author(s):  
Eugene H. Cox ◽  
Mariska W. E. Langemeijer ◽  
Josy M. Gubbens-Stibbe ◽  
Keith T. Muir ◽  
Meindert Danhof
Keyword(s):  
Steady State ◽  
Time Course ◽  
Parent Drug ◽  
Volume Of Distribution ◽  
Pharmacodynamic Model ◽  
Pharmacokinetic Parameters ◽  
Maximal Effect ◽  
Total Blood ◽  
The Mean

Background The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model. Methods Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood. Results Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6). Conclusions Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.

scholarly journals Development of Thalamocortical Response Transformations in the Rat Whisker-Barrel System

2008 ◽  
Vol 99 (1) ◽  
pp. 356-366 ◽  
Author(s):  
Michael Shoykhet ◽  
Daniel J. Simons
Keyword(s):  
Cortical Neurons ◽  
Time Course ◽  
Receptive Fields ◽  
Second Phase ◽  
Adult Rats ◽  
Response Latencies ◽  
Thalamic Neurons ◽  
Response Properties ◽  
Temporal Domain

Extracellular single-unit recordings were used to characterize responses of thalamic barreloid and cortical barrel neurons to controlled whisker deflections in 2, 3-, and 4-wk-old and adult rats in vivo under fentanyl analgesia. Results indicate that response properties of thalamic and cortical neurons diverge during development. Responses to deflection onsets and offsets among thalamic neurons mature in parallel, whereas among cortical neurons responses to deflection offsets become disproportionately smaller with age. Thalamic neuron receptive fields become more multiwhisker, whereas those of cortical neurons become more single-whisker. Thalamic neurons develop a higher degree of angular selectivity, whereas that of cortical neurons remains constant. In the temporal domain, response latencies decrease both in thalamic and cortical neurons, but the maturation time-course differs between the two populations. Response latencies of thalamic cells decrease primarily between 2 and 3 wk of life, whereas response latencies of cortical neurons decrease in two distinct steps—the first between 2 and 3 wk of life and the second between the fourth postnatal week and adulthood. Although the first step likely reflects similar subcortical changes, the second phase likely corresponds to developmental myelination of thalamocortical fibers. Divergent development of thalamic and cortical response properties indicates that thalamocortical circuits in the whisker-to-barrel pathway undergo protracted maturation after 2 wk of life and provides a potential substrate for experience-dependent plasticity during this time.

Responses of primate SI cortical neurons to noxious stimuli

1983 ◽  
Vol 50 (6) ◽  
pp. 1479-1496 ◽  
Author(s):  
D. R. Kenshalo ◽  
O. Isensee
Keyword(s):  
Receptive Field ◽  
Cortical Neurons ◽  
Receptive Fields ◽  
The Body ◽  
Thermal Stimulation ◽  
Discharge Frequency ◽  
Mechanical Stimuli ◽  
Noxious Heat ◽  
Nociceptive Neurons ◽  
Heat Pulses

Recordings were made from single SI cortical neurons in the anesthetized macaque monkey. Each isolated cortical neuron was tested for responses to a standard series of mechanical stimuli. The stimuli included brushing the skin, pressure, and pinch. The majority of cortical neurons responded with the greatest discharge frequency to brushing the receptive field, but neurons were found in areas 3b and 1 that responded maximally to pinching the receptive field. A total of 68 cortical nociceptive neurons were examined in 10 animals. Cortical neurons that responded maximally to pinching the skin were also tested for responses to graded noxious heat pulses (from 35 to 43, 45, 47, and 50 degrees C). If the neuron failed to respond or only responded to 50 degrees C, the receptive field was also heated to temperatures of 53 and 55 degrees C. Fifty-six of the total population of nociceptive neurons were tested for responses to the complete series of noxious heat pulses: 46 (80%) exhibited a progressive increase in the discharge frequency as a function of stimulus intensity, and the spontaneous activity of two (4%) was inhibited. One population of cortical nociceptive neurons possessed restricted, contralateral receptive fields. These cells encoded the intensity of noxious mechanical and thermal stimulation. Sensitization of primary afferent nociceptors was reflected in the responses of SI cortical nociceptive neurons when the ascending series of noxious thermal stimulation was repeated. The population of cortical nociceptive neurons with restricted receptive fields exhibited no adaptation in the response during noxious heat pulses of 47 and 50 degrees C. At higher temperatures the response often continued to increase during the stimulus. The other population of cortical nociceptive neurons was found to have restricted, low-threshold receptive fields on the contralateral hindlimb and, in addition, could be activated only by intense pinching or noxious thermal stimuli delivered on any portion of the body. The stimulus-response functions obtained from noxious thermal stimulation of the contralateral hindlimb were not different from cortical nociceptive neurons with small receptive fields. However, nociceptive neurons with large receptive fields exhibited a consistent adaptation during a noxious heat pulse of 47 and 50 degrees C. Based on the response characteristics of these two populations of cortical nociceptive neurons, we conclude that neurons with small receptive fields possess the ability to provide information about the localization, the intensity, and the temporal attributes of a noxious stimulus.4+.

Leech Mechanosensation

2017 ◽  
Author(s):  
Brian D. Burrell
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Sensory Neurons ◽  
Receptive Fields ◽  
Model Systems ◽  
Sensory Cells ◽  
Mechanical Stimuli ◽  
Nociceptive Neurons ◽  
Mechanosensory Neurons ◽  
The Central Nervous System

The medicinal leech (Hirudo verbana) is an annelid (segmented worm) and one of the classic model systems in neuroscience. It has been used in research for over 50 years and was one of the first animals in which intracellular recordings of mechanosensory neurons were carried out. Remarkably, the leech has three main classes of mechanosensory neurons that exhibit many of the same properties found in vertebrates. The most sensitive of these neurons are the touch cells, which are rapidly adapting neurons that detect low-intensity mechanical stimuli. Next are the pressure cells, which are slow-adapting sensory neurons that respond to higher intensity, sustained mechanostimulation. Finally, there are nociceptive neurons, which have the highest threshold and respond to potentially damaging mechanostimuli, such as a pinch. As observed in mammals, the leech has separate mechanosensitive and polymodal nociceptors, the latter responding to mechanical, thermal, and chemical stimuli. The cell bodies for all three types of mechanosensitive neurons are found in the central nervous system where they are arranged as bilateral pairs. Each neuron extends processes to the skin where they form discrete receptive fields. In the touch and pressure cells, these receptive fields are arranged along the dorsal-ventral axis. For the mechano-only and polymodal nociceptive neurons, the peripheral receptive fields overlap with the mechano-only nociceptor, which also innervates the gut. The leech also has a type of mechanosensitive cell located in the periphery that responds to vibrations in the water and is used, in part, to detect potential prey nearby. In the central nervous system, the touch, pressure, and nociceptive cells all form synaptic connections with a variety of motor neurons, interneurons, and even each other, using glutamate as the neurotransmitter. Synaptic transmission by these cells can be modulated by a variety of activity-dependent processes as well as the influence of neuromodulatory transmitters, such as serotonin. The output of these sensory neurons can also be modulated by conduction block, a process in which action potentials fail to propagate to all the synaptic release sites, decreasing synaptic output. Activity in these sensory neurons leads to the initiation of a number of different motor behaviors involved in locomotion, such as swimming and crawling, as well as behaviors designed to recoil from aversive/noxious stimuli, such as local bending and shortening. In the case of local bending, the leech is able to bend in the appropriate direction away from the offending stimuli. It does so through a combination of which mechanosensory cell receptive fields have been activated and the relative activation of multiple sensory cells decoded by a layer of downstream interneurons.

scholarly journals Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat

2015 ◽  
Vol 113 (1) ◽  
pp. 58-70 ◽  
Author(s):  
Nico A. Jansen ◽  
Glenn J. Giesler
Keyword(s):  
Discharge Rate ◽  
Receptive Fields ◽  
Behavioral Responses ◽  
Spike Timing ◽  
Mustard Oil ◽  
Mechanical Stimuli ◽  
Firing Rates ◽  
Response Characteristics ◽  
Mapping Techniques ◽  
Thermal Stimuli

We tested the possibility that the trigeminoparabrachial tract (VcPbT), a projection thought to be importantly involved in nociception, might also contribute to sensation of itch. In anesthetized rats, 47 antidromically identified VcPbT neurons with receptive fields involving the cheek were characterized for their responses to graded mechanical and thermal stimuli and intradermal injections of pruritogens (serotonin, chloroquine, and β-alanine), partial pruritogens (histamine and capsaicin), and an algogen (mustard oil). All pruriceptive VcPbT neurons were responsive to mechanical stimuli, and more than half were additionally responsive to thermal stimuli. The majority of VcPbT neurons were activated by injections of serotonin, histamine, capsaicin, and/or mustard oil. A subset of neurons were inhibited by injection of chloroquine. The large majority of VcPbT neurons projected to the ipsilateral and/or contralateral external lateral parabrachial and Kölliker-Fuse nuclei, as evidenced by antidromic mapping techniques. Analyses of mean responses and spike-timing dynamics of VcPbT neurons suggested clear differences in firing rates between responses to noxious and pruritic stimuli. Comparisons between the present data and those previously obtained from trigeminothalamic tract (VcTT) neurons demonstrated several differences in responses to some pruritogens. For example, responses of VcPbT neurons to injection of serotonin often endured for nearly an hour and showed a delayed peak in discharge rate. In contrast, responses of VcTT neurons endured for roughly 20 min and no delayed peak of firing was noted. Thus the longer duration responses to 5-HT and the delay in peak firing of VcPbT neurons better matched behavioral responses to stimulation in awake rats than did those of VcTT neurons. The results indicate that VcPbT neurons may have important roles in the signaling of itch as well as pain.

scholarly journals Factors regulating the rat insulin-like growth factor-binding protein-1 response to octreotide

1998 ◽  
Vol 158 (1) ◽  
pp. 61-68
Author(s):  
MS Lewitt ◽  
D Cameron-Smith ◽  
NM Clarke ◽  
H Saunders ◽  
JL Phuyal
Keyword(s):  
Growth Factor ◽  
Time Course ◽  
Binding Protein ◽  
Similar Response ◽  
Insulin Like Growth Factor ◽  
High Fat ◽  
Short Term ◽  
Factor Binding ◽  
The Mean

Insulin-like growth factor-binding protein-1 (IGFBP-1) production is increased by somatostatin and its analogues. In order to determine the time course and identify possible mechanisms of this increase in vivo we administered octreotide to rats and determined IGFBP-1 concentrations by RIA. After 60 min of anaesthesia, the mean baseline IGFBP-1 concentrations were 166 (95% confidence interval 123 to 225) ng/ml and increased in saline-infused animals to 729 (488 to 1086) ng/ml after 180 min. IGFBP-1 was stimulated transiently in response to octreotide, with circulating IGFBP-1 concentrations peaking at 1605 (1220 to 2111) ng/ml at 105 min during a continuous infusion of octreotide (100 micrograms/kg per h). In conscious chronically cannulated rats, baseline IGFBP-1 concentrations were 22 (18 to 28) ng/ml, 8-fold less than in the anaesthetised state, and were stimulated in the short term after administration of an octreotide bolus (100 micrograms/kg s.c.) to reach 88 (62 to 126) ng/ml at 60 min. A similar response was seen after i.v. administration to conscious rats. Intravenous bolus of octreotide (100 micrograms/kg) in rats anaesthetised for 3 h resulted in an increase in IGFBP-1 to peak at 1556 (1268 to 1910) ng/ml at 60 min. The IGFBP-1 response to octreotide was diminished in high-fat fed hyperinsulinaemic rats. The pattern of disappearance of iodinated IGFBP-1 from the circulation was not influenced by octreotide. The changes in GH, insulin and glucose concentrations alone did not sufficiently account for the patterns of response observed. We conclude that, in rats, octreotide stimulates IGFBP-1 acutely and this response is potentiated by factors related to anaesthesia.

Quantitative Analyses of Dynamic Strain Sensitivity in Human Skin Mechanoreceptors

2004 ◽  
Vol 92 (6) ◽  
pp. 3233-3243 ◽  
Author(s):  
Benoni B. Edin
Keyword(s):  
Discharge Rate ◽  
Receptive Fields ◽  
Dynamic Strain ◽  
Strain Sensitivity ◽  
Power Functions ◽  
Discharge Rates ◽  
Response Onset ◽  
Quantitative Analyses ◽  
The Mean ◽  
Skin Mechanoreceptors

Microneurographical recordings from 24 slowly adapting (SA) and 16 fast adapting (FA) cutaneous mechanoreceptor afferents were obtained in the human radial nerve. Most of the afferents innervated the hairy skin on the back of the hand. The afferents' receptive fields were subjected to controlled strains in a ramp-and-hold fashion with strain velocities from 1 to 64% · s−1, i.e., strain velocities within most of the physiological range. For all unit types, the mean variation in response onset approached 1 ms for strain velocities >8% · s−1. Except at the highest strain velocities, the first spike in a typical SAIII unit was evoked at strains <0.5% and a typical SAII unit began to discharge at <1% skin strain. Skin strain velocity had a profound effect on the discharge rates of all classes of afferents. The “typical” peak discharge rate at the highest strain velocity studied was 50–95 imp/s−1 depending on unit type. Excellent fits were obtained for both SA and FA units when their responses to ramp stretches were modeled by simple power functions ( r2 > 0.9 for 95% of the units). SAIII units grouped with SAII with respect to onset latency and onset variation but with SAI units with respect to dynamic strain sensitivity. Because both SA and FA skin afferents respond strongly, quickly, and accurately to skin strain changes, they all seem to be able to provide useful information about movement-related skin strain changes and therefore contribute to proprioception and kinesthesia.

scholarly journals N-Acylethanolamine Acid Amidase Inhibition Potentiates Morphine Analgesia and Delays the Development of Tolerance

2021 ◽  
Author(s):  
Mauro Congiu ◽  
Laura Micheli ◽  
Michele Santoni ◽  
Claudia Sagheddu ◽  
Anna Lisa Muntoni ◽  
...  
Keyword(s):  
Opioid Analgesic ◽  
Morphine Tolerance ◽  
Mechanical Stimuli ◽  
Chronic Morphine ◽  
Analgesic Effects ◽  
Electrophysiological Recordings ◽  
Antinociceptive Effects ◽  
Hydrolyzing Enzymes ◽  
Development Of Tolerance

AbstractOpioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological treatments that enhance opioid analgesic effects and/or attenuate the development of tolerance (with a desirable opioid-sparing effect in treating pain) are actively sought. Among them, N-palmitoylethanolamide (PEA), an endogenous lipid neuromodulator with anti-inflammatory and neuroprotective properties, was shown to exert anti-hyperalgesic effects and to delay the emergence of morphine tolerance. A selective augmentation in endogenous PEA levels can be achieved by inhibiting N-acylethanolamine acid amidase (NAAA), one of its primary hydrolyzing enzymes. This study aimed to test the hypothesis that NAAA inhibition, with the novel brain permeable NAAA inhibitor AM11095, modulates morphine’s antinociceptive effects and attenuates the development of morphine tolerance in rats. We tested this hypothesis by measuring the pain threshold to noxious mechanical stimuli and, as a neural correlate, we conducted in vivo electrophysiological recordings from pain-sensitive locus coeruleus (LC) noradrenergic neurons in anesthetized rats. AM11095 dose-dependently (3–30 mg/kg) enhanced the antinociceptive effects of morphine and delayed the development of tolerance to chronic morphine in behaving rats. Consistently, AM11095 enhanced morphine-induced attenuation of the response of LC neurons to foot-shocks and prevented the attenuation of morphine effects following chronic treatment. Behavioral and electrophysiological effects of AM11095 on chronic morphine were paralleled by a decrease in glial activation in the spinal cord, an index of opioid-induced neuroinflammation. NAAA inhibition might represent a potential novel therapeutic approach to increase the analgesic effects of opioids and delay the development of tolerance.

cGMP modulates basal and activated microvessel permeability independently of [Ca2+]i

1998 ◽  
Vol 274 (6) ◽  
pp. H1865-H1874 ◽  
Author(s):  
P. He ◽  
M. Zeng ◽  
F. E. Curry
Keyword(s):  
Time Course ◽  
Regulatory Mechanisms ◽  
Inflammatory Stimuli ◽  
Cgmp Analog ◽  
Microvessel Permeability ◽  
The Mean ◽  
Mesenteric Microvessels ◽  
Ly 83583 ◽  
Peak Value

To investigate the mechanisms whereby guanosine 3′,5′-cyclic monophosphate (cGMP) modulates microvessel permeability in vivo, we measured changes in microvessel hydraulic conductivity ( L p) and endothelial cytoplasmic Ca2+concentration ([Ca2+]i) in response to the cGMP analogs 8-bromo-cGMP (8-BrcGMP) and 8-( p-chlorophenylthio)cGMP (8-pCPT-cGMP) in the presence and absence of inflammatory stimuli in intact individually perfused microvessels in frog and rat mesenteries. The cGMP analog caused a transient increase in L p and potentiated ATP or bradykinin-induced increases in L p in frog and rat mesenteric microvessels, respectively. The mean peak value of the test L p/control L p after exposure to 8-BrcGMP was 5.3 ± 0.5 in frog microvessels and 2.8 ± 0.4 in rat microvessels. The ATP-induced increase in L p in frog microvessels was further raised by 8-BrcGMP from 7.0 ± 0.9 to 12.4 ± 1.9 times the control. In rat mesenteric microvessels, the bradykinin-induced increase in L p was potentiated by 8-BrcGMP from 4.8 ± 0.4 to 8.3 ± 1.3 times the control and was suppressed by the guanylate cyclase inhibitor LY-83583 to 2.6 ± 0.5 times the control. A similar but larger effect was found when using 8-pCPT-cGMP. In contrast to the actions of increased cGMP on microvessel permeability, cGMP analogs had no effect on basal endothelial [Ca2+]iand did not alter the magnitude and time course of ATP or bradykinin-induced increases in endothelial [Ca2+]i. These results suggested that an elevation of cGMP levels in endothelial cells is a necessary step to increase microvessel permeability in intact microvessels, and this regulatory process occurs downstream from Ca2+ influx, which differs from that reported in large-vessel endothelium in culture and in vascular smooth muscle cells. Experiments carried on microvessels in both frog and rat mesenteries provided a direct comparison of the endothelial cell regulatory mechanisms between species.

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