Diurnal time course of pain perception in healthy humans

As in neocortex and hippocampus, neurons in the dorsal horn of the spinal cord develop long-term potentiation of synaptic efficacy (LTP) on high-frequency stimulation (HFS) of their afferent input, although how long LTP lasts in this nociceptive relay nucleus has not yet been addressed. Here we studied neurogenic hyperalgesia, a perceptual correlate of nociceptive LTP, in 13 healthy subjects, after HFS (5 × 1 s at 100 Hz) of superficial cutaneous afferents. HFS led to a mean upward shift of the stimulus–response function for pinprick-evoked pain (punctate mechanical hyperalgesia) in all subjects by a factor of 2.5 ( P < 0.001) that lasted undiminished for the initial 1-h observation period. Follow-up tests until the next day revealed that this type of neurogenic hyperalgesia decayed with a t1/2 of 3.3 h (99% CI: 3.1–3.5 h) and disappeared completely within 25.4 h (99% CI: 20.4–31.6 h). Touch-evoked pain (dynamic mechanical allodynia) developed in eight of 13 subjects, decayed with a t1/2 of 2.9 h from the maximum and disappeared within 9.3 h. These findings suggest that a single HFS session induces nociceptive LTP in healthy subjects that corresponds to early-LTP (LTP1), implying primarily posttranslational mechanisms for this type of plasticity of human pain perception.

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Left ventricular torsion is equal in mice and humans

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.4.h1117 ◽

2000 ◽

Vol 278 (4) ◽

pp. H1117-H1123 ◽

Cited By ~ 101

Author(s):

R. E. Henson ◽

S. K. Song ◽

J. S. Pastorek ◽

J. J. H. Ackerman ◽

C. H. Lorenz

Keyword(s):

Time Course ◽

Mammalian Species ◽

Tissue Level ◽

Left Ventricular ◽

Ventricular Ejection ◽

Cine Mri ◽

Wall Thickening ◽

Left Ventricular Torsion ◽

Healthy Humans ◽

Ventricular Torsion

Global cardiac function has been studied in small animals with methods such as echocardiography, cine-magnetic resonance imaging (MRI), and cardiac catheterization. However, these modalities make little impact on delineation of pathophysiology at the tissue level. The advantage of tagged cine-MRI technique is that the twisting motion of the ventricle, referred to as torsion, can be measured noninvasively, reflecting the underlying shearing motion of individual planes of myofibrils that generate wall thickening and ventricular ejection. Thus we sought to determine whether the mechanism of ventricular ejection, as measured by torsion, was the same in both humans and mice. Nine mice and ten healthy humans were studied with tagged cine-MRI. The magnitude and systolic time course of ventricular torsion were equivalent in mouse and humans, when normalized for heart rate and ventricular length. The end-systolic torsion angle was 12.7 ± 1.7° in humans vs. 2.0 ± 1.5° in mice unnormalized and 1.9 ± 0.3°/cm vs. 2.7 ± 2.3°/cm when normalized for ventricular length). These results support the premise that ventricular torsion may be a uniform measure of normal ventricular ejection across mammalian species and heart sizes.

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Time course inhibition of gastric and platelet COX activity by acetylsalicylic acid in humans

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.279.5.g1113 ◽

2000 ◽

Vol 279 (5) ◽

pp. G1113-G1120 ◽

Cited By ~ 32

Author(s):

Mark Feldman ◽

Kenneth Shewmake ◽

Byron Cryer

Keyword(s):

Helicobacter Pylori ◽

Acetylsalicylic Acid ◽

Time Course ◽

Pharmacokinetic Profile ◽

Inhibitory Effect ◽

Prostaglandin Synthesis ◽

Controlled Experiment ◽

Peptic Ulcers ◽

Healthy Humans

Aspirin causes peptic ulcers predominately by reducing gastric mucosal cyclooxygenase (COX) activity and prostaglandin synthesis. Because aspirin circulates for only a few hours, we hypothesized that aspirin's inhibitory effect on gastric COX activity must be prolonged. We performed a placebo-controlled experiment in healthy humans to determine the duration of inhibition of aspirin on gastric mucosal COX activity (PGE2 and PGF2α synthesis rates). Recovery of gastric COX activity after stopping aspirin was slow and linear. Seventy-two hours after 325-mg aspirin, gastric COX activity was still reduced by 57% ( P < 0.001). Duration of inhibition of gastric COX activity was estimated to be 7–8 days after 325-mg aspirin and 5 days after 81-mg aspirin. Recovery of gastric prostaglandin synthesis after 325-mg but not after 81-mg aspirin occurred at slower rates in subjects with Helicobacter pylori-associated gastritis than in those with normal histology. In conclusion, aspirin inhibits gastric COX activity for much longer than predicted from its pharmacokinetic profile, explaining why aspirin at widely spaced intervals is ulcerogenic.

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Delta and gamma oscillations in operculo-insular cortex underlie innocuous cold thermosensation

Journal of Neurophysiology ◽

10.1152/jn.00843.2016 ◽

2017 ◽

Vol 117 (5) ◽

pp. 1959-1968 ◽

Cited By ~ 11

Author(s):

Francesca Fardo ◽

Mikkel C. Vinding ◽

Micah Allen ◽

Troels Staehelin Jensen ◽

Nanna Brix Finnerup

Keyword(s):

Evoked Potentials ◽

Time Course ◽

Pain Perception ◽

Functional Integration ◽

Gamma Oscillations ◽

Oscillatory Activity ◽

Neural Pathways ◽

Healthy Human ◽

Central Processing ◽

Evoked Fields

Cold-sensitive and nociceptive neural pathways interact to shape the quality and intensity of thermal and pain perception. Yet the central processing of cold thermosensation in the human brain has not been extensively studied. Here, we used magnetoencephalography and EEG in healthy volunteers to investigate the time course (evoked fields and potentials) and oscillatory activity associated with the perception of cold temperature changes. Nonnoxious cold stimuli consisting of Δ3°C and Δ5°C decrements from an adapting temperature of 35°C were delivered on the dorsum of the left hand via a contact thermode. Cold-evoked fields peaked at around 240 and 500 ms, at peak latencies similar to the N1 and P2 cold-evoked potentials. Importantly, cold-related changes in oscillatory power indicated that innocuous thermosensation is mediated by oscillatory activity in the range of delta (1–4 Hz) and gamma (55–90 Hz) rhythms, originating in operculo-insular cortical regions. We suggest that delta rhythms coordinate functional integration between operculo-insular and frontoparietal regions, while gamma rhythms reflect local sensory processing in operculo-insular areas. NEW & NOTEWORTHY Using magnetoencephalography, we identified spatiotemporal features of central cold processing, with respect to the time course, oscillatory profile, and neural generators of cold-evoked responses in healthy human volunteers. Cold thermosensation was associated with low- and high-frequency oscillatory rhythms, both originating in operculo-insular regions. These results support further investigations of central cold processing using magnetoencephalography or EEG and the clinical utility of cold-evoked potentials for neurophysiological assessment of cold-related small-fiber function and damage.

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Faculty Opinions recommendation of The gene expression and immunohistochemical time-course of diphenylcyclopropenone-induced contact allergy in healthy humans following repeated epicutaneous challenges.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727472237.793547193 ◽

2018 ◽

Author(s):

Jacob Pontoppidan Thyssen

Keyword(s):

Gene Expression ◽

Time Course ◽

Contact Allergy ◽

Healthy Humans

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Combined, but not individual, blockade of ASIC3, P2X, and EP4 receptors attenuates the exercise pressor reflex in rats with freely perfused hindlimb muscles

Journal of Applied Physiology ◽

10.1152/japplphysiol.00630.2015 ◽

2015 ◽

Vol 119 (11) ◽

pp. 1330-1336 ◽

Cited By ~ 16

Author(s):

Audrey J. Stone ◽

Steven W. Copp ◽

Joyce S. Kim ◽

Marc P. Kaufman

Keyword(s):

Lactic Acid ◽

Receptor Antagonist ◽

Time Course ◽

P2x Receptors ◽

Muscle Afferents ◽

P2x Receptor ◽

Exercise Pressor Reflex ◽

Healthy Humans ◽

Ep4 Receptor ◽

Pressor Reflex

In healthy humans, tests of the hypothesis that lactic acid, PGE2, or ATP plays a role in evoking the exercise pressor reflex proved controversial. The findings in humans resembled ours in decerebrate rats that individual blockade of the receptors to lactic acid, PGE2, and ATP had only small effects on the exercise pressor reflex provided that the muscles were freely perfused. This similarity between humans and rats prompted us to test the hypothesis that in rats with freely perfused muscles combined receptor blockade is required to attenuate the exercise pressor reflex. We first compared the reflex before and after injecting either PPADS (10 mg/kg), a P2X receptor antagonist, APETx2 (100 μg/kg), an activating acid-sensing ion channel 3 (ASIC) channel antagonist, or L161982 (2 μg/kg), an EP4 receptor antagonist, into the arterial supply of the hindlimb of decerebrated rats. We then examined the effects of combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the exercise pressor reflex using the same doses, intra-arterial route, and time course of antagonist injections as those used for individual blockade. We found that neither PPADS ( n = 5), APETx2 ( n = 6), nor L161982 ( n = 6) attenuated the reflex. In contrast, combined blockade of these receptors ( n = 7) attenuated the peak (↓27%, P < 0.019) and integrated (↓48%, P < 0.004) pressor components of the reflex. Combined blockade injected intravenously had no effect on the reflex. We conclude that combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the endings of thin fiber muscle afferents is required to attenuate the exercise pressor reflex in rats with freely perfused hindlimbs.

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Peripheral Coding of Tonic Mechanical Cutaneous Pain: Comparison of Nociceptor Activity in Rat and Human Psychophysics

Journal of Neurophysiology ◽

10.1152/jn.1999.82.5.2641 ◽

1999 ◽

Vol 82 (5) ◽

pp. 2641-2648 ◽

Cited By ~ 63

Author(s):

David Andrew ◽

Joel D. Greenspan

Keyword(s):

Pain Intensity ◽

Temporal Summation ◽

Time Course ◽

Pain Perception ◽

Human Subjects ◽

Conduction Block ◽

Stimulus Onset ◽

Mechanical Stimuli ◽

Electrophysiological Recordings ◽

C Fiber

These experiments investigated temporal summation mechanisms of tonic cutaneous mechanical pain. Human volunteers provided psychophysical estimates of pain intensity, which were compared with discharge patterns of rat cutaneous nociceptors tested with identical stimulus protocols. Human subjects made either intermittent or continuous ratings of pain intensity during stimulation of the skin between the thumb and first finger. Stimulus intensities of 25, 50, and 100 g were applied with a probe of contact area of 0.1 mm2 for 2 min. Pain perception significantly increased during stimulation (temporal summation) for the 50- and 100-g stimulus intensities. Sequential conduction block of the myelinated fibers supplying the stimulated skin was used to investigate the role of A-fiber mechanoreceptors and nociceptors in this temporal summation. Conduction block of the Aβ fibers resulted in an increase in mechanically evoked pain estimates and an increase in temporal summation, consistent with loss of Aβ-mediated inhibition. When only conduction in the unmyelinated fibers remained, pain estimates were reduced to the preblock levels, but temporal summation was still present. Electrophysiological recordings were made from filaments of the sciatic nerve supplying receptors in the plantar skin of barbiturate-anesthetized rats. Forty units fulfilled the identification criteria for nociceptors: 20 A-fiber and 20 C-fiber nociceptors. Each unit was characterized by recording its responses to graded mechanical and heat stimuli. Nociceptors were also tested with stimuli identical to those applied to the human subjects. The responses of all units to sustained mechanical stimuli were adaptive—that is, they exhibited a gradual decline in response with time. However, the time course of adaptation varied among units. All the C-fiber nociceptors and one-half of the A-fiber nociceptors had rapidly adapting responses. The remainder of the A-fibers displayed slowly adapting responses. One-third of all units also showed short-duration increases in firing rate during stimulation. The latency after stimulus onset of this rate acceleration was inversely related to stimulus intensity. Despite the apparent disparity between perceptual temporal summation and nociceptor adaptation, central and peripheral mechanisms are proposed that can reconcile the relationship between nociceptor activity and pain perception.

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