Thermonociceptive Stimuli Research Articles

Cue-based modulation of pain stimulus expectation: do ongoing oscillations reflect changes in pain perception? A registered report.

A promising stream of investigations is targeting ongoing neural oscillations and whether their modulation could be related to the perception of pain. Using an electroencephalography (EEG) frequency-tagging approach, sustained periodic thermonociceptive stimuli perceived as painful have been shown to modulate ongoing oscillations in the theta, alpha and beta bands at the frequency of stimulation. Nonetheless, it remains uncertain whether these modulations are indeed linked to pain perception. To test this relationship, we modulated pain perception using a cue-based expectation modulation paradigm and investigated whether ongoing oscillations in different frequency bands mirror the changes in stimulus perception. Forty healthy participants were instructed that a visual cue can precede either a high- or low-intensity stimulation. These cues were paired with three different levels of sustained periodic thermonociceptive stimuli (low, medium and high). Despite a strong effect of expectation on perceived stimulus intensity, this effect was not reflected in the modulation of the ongoing oscillations, suggesting a potential dissociation of pain perception and these oscillatory activities. Rather, it seems that the intensity of stimulation is the primary generator of the frequency-tagged EEG responses. Importantly, these results need to be confirmed by further investigations that could allow the detection of smaller effects than originally estimated.

Neural processes responsible for the translation of sustained nociceptive inputs into subjective pain experience.

Tracking and predicting the temporal structure of nociceptive inputs is crucial to promote survival, as proper and immediate reactions are necessary to avoid actual or potential bodily injury. Neural activities elicited by nociceptive stimuli with different temporal structures have been described, but the neural processes responsible for translating nociception into pain perception are not fully elucidated. To tap into this issue, we recorded electroencephalographic signals from 48 healthy participants receiving thermo-nociceptive stimuli with 3 different durations and 2 different intensities. We observed that pain perception and several brain responses are modulated by stimulus duration and intensity. Crucially, we identified 2 sustained brain responses that were related to the emergence of painful percepts: a low-frequency component (LFC, < 1Hz) originated from the insula and anterior cingulate cortex, and an alpha-band event-related desynchronization (α-ERD, 8-13Hz) generated from the sensorimotor cortex. These 2 sustained brain responses were highly coupled, with the α-oscillation amplitude that fluctuated with the LFC phase. Furthermore, the translation of stimulus duration into pain perception was serially mediated by α-ERD and LFC. The present study reveals how brain responses elicited by nociceptive stimulation reflect the complex processes occurring during the translation of nociceptive information into pain perception.

Insular responses to transient painful and non-painful thermal and mechanical spinothalamic stimuli recorded using intracerebral EEG

Brief thermo-nociceptive stimuli elicit low-frequency phase-locked local field potentials (LFPs) and high-frequency gamma-band oscillations (GBOs) in the human insula. Although neither of these responses constitute a direct correlate of pain perception, previous findings suggest that insular GBOs may be strongly related to the activation of the spinothalamic system and/or to the processing of thermal information. To disentangle these different features of the stimulation, we compared the insular responses to brief painful thermonociceptive stimuli, non-painful cool stimuli, mechano-nociceptive stimuli, and innocuous vibrotactile stimuli, recorded using intracerebral electroencephalograpic activity in 7 epileptic patients (9 depth electrodes, 58 insular contacts). All four types of stimuli elicited consistent low-frequency phase-locked LFPs throughout the insula, possibly reflecting supramodal activity. The latencies of thermo-nociceptive and cool low-frequency phase-locked LFPs were shorter in the posterior insula compared to the anterior insula, suggesting a similar processing of thermal input initiating in the posterior insula, regardless of whether the input produces pain and regardless of thermal modality. In contrast, only thermo-nociceptive stimuli elicited an enhancement of insular GBOs, suggesting that these activities are not simply related to the activation of the spinothalamic system or to the conveyance of thermal information.

Cellular Mechanism for Specific Mechanical Antinociception by D2-like Receptor at the Spinal Cord Level

Intrathecal (i.t.) administration of quinpirole, a dopamine (DA) D2-like receptor agonist, produces antinociception to mechanonociceptive stimuli but not to thermonociceptive stimuli. To determine a cellular mechanism for the specific antinociceptive effect of D2-like receptor activation on mechanonociception, we evaluated the effect of quinpirole on voltage-gated Ca2+ influx in cultured dorsal root ganglion (DRG) neurons and the D2 DA receptor distribution in subpopulations of rat nociceptive DRG neurons.Small-diameter DRG neurons were classified into IB4+ (nonpeptidergic) and IB4- (peptidergic). Intracellular [Ca2+] microfluorometry and voltage-clamp experiments showed that quinpirole reduced Ca2+ influx and inhibited the high voltage-activated Ca2+ current (HVA-ICa) in half of IB4+ neurons, leaving Ca2+ entry and HVA-ICa in IB4- neurons nearly unaffected. Pretreatment with ω-conotoxin MVIIA prevented the effect of quinpirole on HVA-ICa from IB4+ neurons, indicating that quinpirole mainly inhibits CaV2.2 channels. Immunofluorescence experiments showed that D2 DA receptor was present mainly in IB4+ small DRG neurons. Finally, in behavioral experiments in rats, the clinically approved D2-like receptor agonist pramipexole produced spinal antinociception in a similar fashion to quinpirole, with a significant effect only in the mechanonociceptive test. Our results explain, at least in part, why D2-like receptor agonists produce antinociception on mechanonociceptors.

Gamma-Band Oscillations Preferential for Nociception can be Recorded in the Human Insula.

Transient nociceptive stimuli elicit robust phase-locked local field potentials (LFPs) in the human insula. However, these responses are not preferential for nociception, as they are also elicited by transient non-nociceptive vibrotactile, auditory, and visual stimuli. Here, we investigated whether another feature of insular activity, namely gamma-band oscillations (GBOs), is preferentially observed in response to nociceptive stimuli. Although nociception-evoked GBOs have never been explored in the insula, previous scalp electroencephalography and magnetoencephalography studies suggest that nociceptive stimuli elicit GBOs in other areas such as the primary somatosensory and prefrontal cortices, and that this activity could be closely related to pain perception. Furthermore, tracing studies showed that the insula is a primary target of spinothalamic input. Using depth electrodes implanted in 9 patients investigated for epilepsy, we acquired insular responses to brief thermonociceptive stimuli and similarly arousing non-nociceptive vibrotactile, auditory, and visual stimuli (59 insular sites). As compared with non-nociceptive stimuli, nociceptive stimuli elicited a markedly stronger enhancement of GBOs (150-300 ms poststimulus) at all insular sites, suggesting that this feature of insular activity is preferential for thermonociception. Although this activity was also present in temporal and frontal regions, its magnitude was significantly greater in the insula as compared with these other regions.

High-frequency electrical stimulation of the human skin induces heterotopical mechanical hyperalgesia, heat hyperalgesia, and enhanced responses to nonnociceptive vibrotactile input

High-frequency electrical stimulation (HFS) of the human skin induces increased pain sensitivity in the surrounding unconditioned skin. The aim of the present study was to characterize the relative contribution of the different types of nociceptive and nonnociceptive afferents to the heterotopical hyperalgesia induced by HFS. In 17 healthy volunteers (9 men and 8 women), we applied HFS to the ventral forearm. The intensity of perception and event-related brain potentials (ERPs) elicited by vibrotactile stimuli exclusively activating nonnociceptive low-threshold mechanoreceptors and thermonociceptive stimuli exclusively activating heat-sensitive nociceptive afferents were recorded before and after HFS. The previously described mechanical hyperalgesia following HFS was confirmed by measuring the changes in the intensity of perception elicited by mechanical punctate stimuli. HFS increased the perceived intensity of both mechanical punctate and thermonociceptive stimuli applied to the surrounding unconditioned skin. The time course of the effect of HFS on the perception of mechanical and thermal nociceptive stimuli was similar. This indicates that HFS does not only induce mechanical hyperalgesia, but also induces heat hyperalgesia in the heterotopical area. Vibrotactile ERPs were also enhanced after HFS, indicating that nonnociceptive somatosensory input could contribute to the enhanced responses to mechanical pinprick stimuli. Finally, the magnitude of thermonociceptive ERPs was unaffected by HFS, indicating that type II A-fiber mechano-heat nociceptors, thought to be the primary contributor to these brain responses, do not significantly contribute to the observed heat hyperalgesia.

Pathophysiology of Neuropathic Pain in Type 2 Diabetes

OBJECTIVENeuropathic pain due to small-fiber sensory neuropathy in type 2 diabetes can be diagnosed by skin biopsy with quantification of intra-epidermal nerve fiber (IENF) density. There is, however, a lack of noninvasive physiological assessment. Contact heat–evoked potential (CHEP) is a newly developed approach to record cerebral responses of Aδ fiber–mediated thermonociceptive stimuli. We investigated the diagnostic role of CHEP.RESEARCH DESIGN AND METHODSFrom 2006 to 2009, there were 32 type 2 diabetic patients (20 males and 12 females, aged 51.63 ± 10.93 years) with skin denervation and neuropathic pain. CHEPs were recorded with heat stimulations at the distal leg, where skin biopsy was performed.RESULTSCHEP amplitude was reduced in patients compared with age- and sex-matched control subjects (14.8 ± 15.6 vs. 33.7 ± 10.1 μV, P < 0.001). Abnormal CHEP patterns (reduced amplitude or prolonged latency) were noted in 81.3% of these patients. The CHEP amplitude was the most significant parameter correlated with IENF density (P = 0.003) and pain perception to contact heat stimuli (P = 0.019) on multiple linear regression models. An excitability index was derived by calculating the ratio of the CHEP amplitude over the IENF density. This excitability index was higher in diabetic patients than in control subjects (P = 0.023), indicating enhanced brain activities in neuropathic pain. Among different neuropathic pain symptoms, the subgroup with evoked pain had higher CHEP amplitudes than the subgroup without evoked pain (P = 0.011).CONCLUSIONSCHEP offers a noninvasive approach to evaluate the degeneration of thermonociceptive nerves in diabetic neuropathy by providing physiological correlates of skin denervation and neuropathic pain.

Functional magnetic resonance imaging and diffusion tensor imaging in a case of central poststroke pain

The role of the lesion location within functional pain systems is not fully understood for central poststroke pain (CPSP) pathogenesis. In a patient with CPSP we used data from both functional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) for anatomo-functional correlations. Structural MRI showed a small residual cavity confined to the right thalamic ventral posterolateral nucleus and the adjacent posterior arm of the internal capsule. DTI maps showed selective reduction of right sensory thalamocortical fibers. Functional MRI, performed with different thermonociceptive stimuli, showed pain-specific signal changes in the anterior cingulate gyrus (BA 24/32) and in the associative parietal regions (BA 5/7). These findings underline, for CPSP pathogenesis, the role of damage of lateral nociceptive thalamoparietal fibers together with the release of activity of anterior cingulate and posterior parietal regions. Perspective In a patient with CPSP, we combined noninvasive neuroimaging techniques (functional and diffusion MRI) to assess the anatomo-functional relationship in CPSP. Our investigations show, for CPSP pathogenesis, the role of damage of lateral nociceptive thalamoparietal fibers together with the release of activity of anterior cingulate and posterior parietal regions.

Strain differences in the hyperalgesic effect of a novel kappa receptor agonist, U-50488H in mice.

The administration of a kappa agonist, U- 50488H produced reduction in jumping latencies in the hot plate test in Swiss and CBA strains of mice but not in CXBH , CXBK and C57BL strains. The hyperalgesia following U- 50488H in Swiss and CBA strains might possibly be related to the antagonism of endogenous substrates for kappa receptors released during the thermonociceptive stimuli. A detailed time-course study in Swiss Strain revealed that a significant hyperalgesia was observable from 10 min up to 2 h. The present results indicate that CXBH , CXBK and C57BL strains might be deficient in kappa ligands and/or receptor levels relevant to thermonociception .