Noxious Conditioning Stimulation Research Articles

Physical Activity Is Predictive of Conditioned Pain Modulation in Healthy Individuals: A Cross-Sectional Study

Even in healthy populations, conditioned pain modulation (CPM) magnitude varies. This may be accounted for by (non-)modifiable factors, including physical activity (PA). Yet, little research has thoroughly examined PA and its relation with CPM magnitude in a representative sample. Therefore, the present study investigated the predictive effect of PA on CPM magnitude in 105 healthy adults. PA was assessed during 7 consecutive days by self-report using the International Physical Activity Questionnaire and by monitor-based accelerometry. CPM was examined using a heterotopic noxious-conditioning stimulation protocol during which the effect of a hot water-conditioning stimulus on pressure pain thresholds was evaluated. Comparative, correlation, and hierarchical linear regression analyses were performed. Report-based walking predicts 4.8% of variance in pain-modulatory capacity, moderate PA predicts 10.2% of variance in pain-modulatory capacity, and report-based time spent on total PA predicts 7.0% of variance in pain-modulatory capacity. More metabolic equivalent-minutes/week spent on total PA, including walking and moderate PA, is associated with greater pain-modulatory capacity. The findings of this study add to the limited evidence on the predictive effect of PA on CPM. It urges to consider PA a confounding factor when examining CPM. The current study provides evidence that a physically active lifestyle benefits endogenous pain modulation in healthy adults. Given its potential, walking and moderate-intensity PA might be achievable treatment strategies for pain patients known to have impaired CPM. PerspectiveThe results of this article show that a physically active lifestyle, including larger amounts of walking and moderate activity, predicts greater pain-modulatory capacity. Trial RegistrationThis study has not been preregistered.

Abnormalities of the Descending Inhibitory Nociceptive Pathway in Functional Motor Disorders.

Pain is a common disabling non-motor symptom affecting patients with functional motor disorders (FMD). We aimed to explore ascending and descending nociceptive pathways with laser evoked potentials (LEPs) in FMD. We studied a "bottom-up and top-down" noxious paradigm applying a conditioned pain modulation (CPM) protocol and recorded N2/P2 amplitude in 21 FMD and 20 controls following stimulation of both right arm and leg at baseline (BS) (bottom-up), during heterotopic noxious conditioning stimulation (HNCS) with ice test (top-down) and post-HNCS. We found a normal ascending pathway, but reduced CPM response (lower reduction of the N2/P2 amplitude) in FMD patients, by stimulating both upper and lower limbs. The N2/P2 amplitude ratio*100 (between the HNCS and BS) was significantly higher in patients with FMD than HC. Our results suggest that pain in FMD possibly reflects a descending pain inhibitory control impairment, therefore, providing a novel venue to explore the pathophysiology of pain in FMD. © 2024 International Parkinson and Movement Disorder Society.

Defect of the Endogenous Inhibitory Pain System in Idiopathic Restless Legs Syndrome: A Laser Evoked Potentials Study.

Restless legs syndrome (RLS) is a complex sensorimotor disorder. Symptoms worsen toward evening and at rest and are temporarily relieved by movement. Symptoms are perceived as painful in up to 45% of cases, and nociception system may be involved. To assess the descending diffuse noxious inhibitory control in RLS patients. Twenty-one RLS patients and twenty age and sex-matched healthy controls (HC) underwent a conditioned pain modulation protocol. Cutaneous heat stimuli were delivered via laser evoked potentials (LEPs) on the dorsum of the right hand (UL) and foot (LL). N2 and P2 latencies, N2/P2 amplitude and pain ratings (NRS) were recorded before (baseline), during, and after a heterotopic noxious conditioning stimulation (HNCS) application. The baseline/HNCS ratio was calculated for both UL and LL. N2 and P2 latencies did not vary between groups at each condition and limbs. Both groups showed a physiological N2/P2 amplitude and NRS reduction during the HNCS condition in UL and LL in comparison to baseline and post conditions (all, P < 0.003). Between-groups comparisons revealed a significant lower amplitude reduction in RLS at the N2/P2 amplitude during the HNCS condition only for LL (RLS, 13.6 μV; HC, 10.1 μV; P = 0.004). Such result was confirmed by the significant difference at the ratio (RLS, 69%, HC, 52.5%; P = 0.038). The lower physiological reduction during the HNCS condition at LL in RLS patients suggests a defect in the endogenous inhibitory pain system. Further studies should clarify the causal link of this finding, also investigating the circadian modulation of this paradigm. © 2023 International Parkinson and Movement Disorder Society.

The N13 spinal component of somatosensory evoked potentials is modulated by heterotopic noxious conditioning stimulation suggesting an involvement of spinal wide dynamic range neurons

ObjectivesAlthough somatosensory evoked potentials (SEPs) after median nerve stimulation are widely used in clinical practice, the dorsal horn generator of the N13 SEP spinal component is not clearly understood. To verify whether wide dynamic range neurons in the dorsal horn of the spinal cord are involved in the generation of the N13 SEP, we tested the effect of heterotopic noxious conditioning stimulation, which modulates wide dynamic range neurons, on N13 SEP in healthy humans. MethodsIn 12 healthy subjects, we performed the cold pressor test on the left foot as a heterotopic noxious conditioning stimulus to modulate wide dynamic range neurons. To verify the effectiveness of heterotopic noxious conditioning stimulation, we tested the pressure pain threshold at the thenar muscles of the right hand and recorded SEPs after right median nerve stimulation before, during and after the cold pressor test. ResultsThe cold pressor test increased pressure pain threshold by 15% (p = 0.04). During the cold pressor test, the amplitude of the N13 component was significantly lower than that recorded at baseline (by 25%, p = 0.04). DiscussionIn this neurophysiological study in healthy humans, we showed that a heterotopic noxious conditioning stimulus significantly reduced N13 SEP amplitude. This finding suggests that the N13 SEP might be generated by the segmental postsynaptic response of dorsal horn wide dynamic range neurons.

Conditioned pain modulation affects the N2/P2 complex but not the N1 wave: A pilot study with laser-evoked potentials.

The 'pain-inhibits-pain' effect stems from neurophysiological mechanisms involving endogenous modulatory systems termed diffuse noxious inhibitory controls (DNIC) or conditioned pain modulation (CPM). Laser-evoked potentials (LEPs) components, the N2/P2 complex, and the N1 wave, reflect the medial and lateral pain pathway, respectively: anatomically, the lateral thalamic nuclei (LT) project mainly to the somatosensory cortex (N1 generator), while the medial thalamic nuclei (MT) are bound to the limbic cortices (N2/P2 generators). We applied a CPM protocol in which the test stimulus was laser stimulation and the conditioning stimulus was a cold pressor test. LEPs recordings were obtained from 15 healthy subjects in three different conditions: baseline, during heterotopic noxious conditioning stimulation (HNCS) and post-HNCS. We observed a significant reduction in N2/P2 amplitude during HNCS and a return to pre-test amplitude post-HNCS, whereas the N1 wave remained unchanged during and post-HNCS. Our results indicate that CPM affects only the medial pain system. The spinothalamic tract (STT) transmits to both the LT and the MT, while the spinoreticulothalamic (SRT) projects only to the MT. The reduction in the amplitude of the N2/P2 complex and the absence of change in the N1 wave suggest that DNIC inhibition on the dorsal horn neurons affects only pain transmission via the SRT, while the neurons that give rise to the STT are not involved. The N1 wave can be a reliable neurophysiological parameter for assessment of STT function in clinical practice, as it does not seem to be influenced by CPM. No reports have described the effect of DNIC on lateral and medial pain pathways. We studied the N1 wave and the N2/P2 complex to detect changes during a CPM protocol. We found a reduction in the amplitude of the N2/P2 complex and no change in the N1 wave. This suggests that the DNIC inhibitory effect on dorsal horns neurons affects only pain transmission via the SRT, whereas the neurons that give rise to the STT are not involved.

Intense and sustained pain reduces cortical responses to auditory stimuli: Implications for the interpretation of the effects of heterotopic noxious conditioning stimulation in humans.

Phasic pain stimuli are inhibited when they are applied concomitantly with a conditioning tonic stimulus at another body location (heterotopic noxious conditioning stimulation, HNCS). While the effects of HNCS are thought to rely on a spino-bulbo-spinal mechanism in animals (termed diffuse noxious inhibitory controls, DNIC), the underlying neurophysiology in humans may involve other pathways. In this study, we investigated the role of concomitant supraspinal mechanisms during HNCS by presenting auditory stimuli during a conditioning tonic painful stimulus (the cold pressor test, CPT). Considering that auditory stimuli are not conveyed through the spinal cord, any changes in brain responses to auditory stimuli during HNCS can be ascribed entirely to supraspinal mechanisms. Electroencephalography (EEG) was recorded during HNCS, and auditory stimuli were administered in three blocks, before, during and after HNCS. Nociceptive withdrawal reflexes (NWRs) were recorded at the same time points to investigate spinal processing. Our results showed that AEPs were significantly reduced during HNCS. Moreover, the amplitude of the NWR was significantly diminished during HNCS in most participants. Given that spinal and supraspinal mechanisms operate concomitantly during HNCS, the possibility of isolating their individual contributions in humans is questionable. We conclude that the net effects of HCNS are not independent from attentional/cognitive influences.

Pain in cervical dystonia: Evidence of abnormal inhibitory control

IntroductionSeveral observations would suggest that dystonic pain is not simply muscular in origin. While ascending nociceptive pathways are normal in cervical dystonia, it is unknown whether descending inhibitory pain pathways are also normal. MethodsWe applied a conditioned pain modulation protocol and concomitantly recorded laser evoked potentials in patients with cervical dystonia (n = 15), blepharospasm (n = 15) and healthy volunteers (n = 15). ResultsDuring the application of a heterotopic noxious conditioning stimulation, patients with cervical dystonia, but not with blepharospasm, lacked the physiological reduction of the perceived intensity of a painful test stimulus as well as of the related evoked potential. This was observed in cervical dystonia patients regardless of the presence of clinical pain. ConclusionsOur results suggest that pain in CD is not simply muscular in origin but it also possibly reflects a dysfunction of the descending pain inhibitory control, thus providing a novel venue to explore the pathophysiology of pain in CD.

A novel paradigm to evaluate conditioned pain modulation in fibromyalgia.

IntroductionApplication of noxious stimulation to one body area reduces pain sensitivity in a remote body area through activation of an endogenous pain-inhibitory network, a behavioral phenomenon referred to as conditioned pain modulation (CPM). The efficiency of CPM is predictive of a variety of health outcomes, while impaired CPM has been associated with various chronic pain conditions. Current methods used to assess CPM vary widely, and interest in CPM method development remains strong. Here, we evaluated a novel method for assessing CPM in healthy controls and fibromyalgia (FM) patients using thumb pressure as both a test and conditioning stimulus.MethodsSixteen female FM patients and 14 matched healthy controls underwent CPM testing with thumbnail pressure as the test stimulus, and either cold water or noxious pressure as the conditioning stimulus. CPM magnitude was evaluated as the difference in pain rating of the test stimulus applied before and during the conditioning stimulus.ResultsIn healthy controls, application of either pressure or cold water conditioning stimulation induced CPM as evidenced by a significant reduction in test stimulus pain rating during conditioning (P=0.007 and P=0.021, respectively). In contrast, in FM patients, neither conditioning stimulus induced a significant CPM effect (P>0.274). There was a significant difference in CPM magnitude for FM patients compared to healthy controls with noxious pressure conditioning stimulation (P=0.023); however, no significant difference in CPM was found between groups using cold water as a conditioning stimulus (P=0.269).ConclusionThe current study demonstrates that thumbnail pressure can be used as both a test and conditioning stimulus in the assessment of CPM. This study further confirms previous findings of attenuated CPM in FM patients compared with healthy controls.

The antalgic effects of non-invasive physical modalities on central post-stroke pain: a systematic review.

[Purpose] This study systematically reviewed the antalgic effects of non-invasive physical modalities (NIPMs) on central post-stroke pain (CPSP). [Subjects and Methods] Clinical studies were sought on September 2015 in 10 electronic databases, including Medline and Scopus. The searching strings were “central pain and stroke” and “treatment, and physical or non-pharmacological”. The inclusion and exclusion criteria were set for screening the clinical articles by two reviewers. Pain scores on visual analog scale in an article were used as the outcome measure for resulting judgment. The NIPMs intervention summarized from the eligible articles was rated from Levels A to C according to Evidence Classification Scheme for Therapeutic Interventions. [Results] Over 1200 articles were identified in the initial searches and 85 studies were retrieved. Sixteen studies were eligible and judged. Caloric vestibular stimulation (n=3), heterotopic noxious conditioning stimulation (n=1), and transcutaneous electrical stimulation (n=1) were rated below Level C. Transcranial direct current stimulation (TDCS; n=2) and transcranial magnetic stimulation (TMS; n=9) were rated as Level B. [Conclusion] The findings suggest that TMS and TDCS were better than other treatments for CPSP relief but the studies were of insufficient quality.

The effect of heterotopic noxious conditioning stimulation on Aδ-, C- and Aβ-fibre brain responses in humans.

Human studies have shown that heterotopic nociceptive conditioning stimulation (HNCS) applied to a given body location reduces the percept and brain responses elicited by noxious test stimuli delivered at a remote body location. It remains unclear to what extent this effect of HNCS relies on the spinal-bulbar-spinal loop mediating the effect of diffuse noxious inhibitory controls (DNICs) described in animals, and/or on top-down cortical mechanisms modulating nociception. Importantly, some studies have examined the effects of HNCS on the brain responses to nociceptive input conveyed by Aδ-fibres. In contrast, no studies have explored the effects of HNCS on the responses to selective nociceptive C-fibre input and non-nociceptive Aβ-fibre input. In this study, we measured the intensity of perception and event-related potentials (ERPs) to stimuli activating Aδ-, C- and Aβ-fibres, before, during and after HNCS, obtained by immersing one foot in painful cold water. We observed that (i) the perceived intensity of nociceptive Aδ- and C-stimuli was reduced during HNCS, and (ii) the ERPs elicited by Aδ- and Aβ- and C-stimuli were also reduced during HNCS. Importantly, because Aβ-ERPs are related to primary afferents that ascend directly through the dorsal columns without being relayed at spinal level, the modulation of these responses may not be explained by an influence of descending projections modulating the transmission of nociceptive input at spinal level. Therefore, our results indicate that, in humans, HNCS should be used with caution as a direct measure of DNIC-related mechanisms.

Effects of Different Anesthetics on Pain Processing in an Experimental Human Pain Model.

After surgical procedures, anesthesia itself may affect pain perception. Particularly, there is increasing evidence that opioids not only have analgesic effects but also provoke pronociceptive changes, that is, opioid-induced hyperalgesia. We investigated the effect of different anesthetic regimens on pain processing in volunteers using a transdermal electrical pain model. In this model, stimulation of epidermal nerve fibers representing mainly peptidergic C-nociceptors leads to secondary hyperalgesia and habituation to the stimulus. Forty-eight healthy volunteers underwent conditioning noxious stimulation (CS) over 5days. On day 2, the volunteers were randomized into 4 groups: control group (no anesthesia) and 3 groups receiving anesthesia before CS in anesthetic doses: propofol (P), propofol/remifentanil (PR), and propofol/remifentanil/S-ketamine (PRK). Quantitative sensory testing was performed on days 1 through 5 and on day 22. In every group, CS was associated with short- and long-term habituation to the electrical stimulus. Repetitive CS resulted in unmodified short-term sensitization with stable areas of hyperalgesia. Although the PR group showed a trend toward increased areas of hyperalgesia on day 2, no significant differences were detectable between the groups. In contrast, anesthesia resulted in decreased intensity of the electrically evoked pain on day 2. Finally, the mechanical pain threshold before CS on day 5 was increased in all groups and remained elevated 3weeks after the first CS, consistent with a long-term antinociceptive effect after CS. The results suggest a short-term analgesic effect of general anesthesia. Furthermore, the conditioning stimulation over several days induced differential modulation of pro- and antinociceptive systems.

Dysfunctional pain inhibition in patients with chronic whiplash-associated disorders: an experimental study

Inefficient endogenous pain inhibition, in particular impaired conditioned pain modulation (CPM), may disturb central pain processing in patients with chronic whiplash-associated disorders (WAD). Previous studies revealed that abnormal central pain processing is responsible for a wide range of symptoms in patients with chronic WAD. Hence, the present study aimed at examining the functioning of descending pain inhibitory pathways, and in particular CPM, in patients with chronic WAD. Thirty-five patients with chronic WAD and 31 healthy controls were subjected to an experiment evaluating CPM. CPM was induced by an inflated occlusion cuff and evaluated by comparing temporal summation (TS) of pressure pain prior to and during cuff inflation. Temporal summation was provoked by means of 10 consecutive pressure pulses at upper and lower limb location. Pain intensity of first, fifth, and 10th pressure pulse was rated. During heterotopic noxious conditioning stimulation, TS of pressure pain was significantly depleted among healthy controls. In contrast, TS was quite similar prior to and during cuff inflation in chronic WAD, providing evidence for dysfunctional CPM in patients with chronic WAD. The present study demonstrates a lack of endogenous pain inhibitory pathways, and in particularly CPM, in patients with chronic WAD, and hence provides additional evidence for the presence of central sensitization in chronic WAD.

The effect of a mental stressor on conditioned pain modulation in healthy subjects

Background and purposeIn animal studies, enhanced sensitivity to painful stimuli succeeding chronic stress has been reported, while acute stress is reported to induce analgesia. Human studies on the effect of mental stress on pain are more equivocal. A disturbed stress-response resulting in an increased sensitivity to painful stimuli has also been discussed as a potential mechanism for e.g., the fibromyalgia syndrome. Endogenous analgesia may be studied in humans by measuring the analgesic effect of heterotopic noxious conditioning stimulation. In neurophysiological animal studies this phenomenon was originally denoted “diffuse noxious inhibitory controls” (DNIC), but for human studies it has been suggested to use the term conditioned pain modulation (CPM).The clinical relevance of aberrances in CPM is not clear. Inhibitory CPM is reported as being reduced in several medically unexplained syndromes with musculoskeletal pain aggravated by mental stress. However, whether the reported reduced CPM effects are causally related to clinical pain is unknown.In the present study the effect of a mental stressor on CPM is studied. MethodsWith tourniquet-induced pain as the conditioning stimulus we estimated the CPM effect in twenty healthy subjects. Heat pain threshold (HPT), supra-threshold heat pain level (SHPL) and pressure pain threshold (PPT) were used as test stimuli. Measurements were performed at baseline, after a stressful task and after a non-stressful task presented in a blinded cross-over design. We used repeated-measures ANOVAs in the analysis with simple contrasts for post hoc analysis. ResultsWith a ANOVA repeated measures model we found a significant task effect (F=18.5, p≤0.001), indicating that CPM was successfully induced. In our ANOVA model, we found a significant effect of stress in the contrast analysis (F=5.2, p=0.037), indicating that CPM was affected by the stressful task. The effects on PPT could not be analyzed due to a significant carry-over effect (for PPT only). ConclusionsIn the present blinded crossover study, we found a significant small to medium inhibitory effect of mental stress upon the CPM of thermal pain. ImplicationsOur results suggest that previously reported reduced inhibitory CPM in several medically unexplained syndromes with musculoskeletal pain aggravated by mental stress possibly can be related to confounding or clinically relevant stress level differences. However, the result might be modality-specific. Further studies in patients are obviously needed, and the impact of mental stress on CPM should be investigated also with other stressors.

Development of a bedside sensory testing kit for postherpetic neuralgia

Postherpetic Neuralgia (PHN) is a heterogeneous and complex pain syndrome that involves various pain mechanisms. It is believed that PHN patients could be classified into different sensory profiles using quantitative sensory testing. Because no standardized, comprehensive sensory assessment easily performed at bedside exists for PHN, we developed a Bedside Sensory Testing Kit for PHN (BSTK-PHN) to classify patients with PHN based on presence of peripheral and/or central sensitization. The kit was tested in a usability and informal (not powered) reliability study in 12 PHN patients. Subjects completed a neuropathic pain questionnaire and underwent sensory testing with the BSTK-PHN, which involves measuring (i) static and dynamic mechanical allodynia using a pressure algometer, (ii) punctate hyperalgesia via pinprick, (iii) low-threshold mechanoreceptive function using von Frey filaments; (iv) cold allodynia using a brass rod; (v) wind-up to temporal summation using the von Frey filaments; and (vi) diffuse noxious inhibitory control (DNIC) after heterotopic noxious conditioning stimulation (HNCS) using a pressure algometer. The BSTK-PHN assessments had a highly acceptable level of tolerability and usability for both subjects and investigators. Inter-rater reliability (kappa analysis) was above the pre-specified acceptability threshold for all assessments of the BSTK-PHN (>0.70), except for the DNIC, which was slightly below 0.70. Subjects appeared to cluster into discrete subgroups (based on the presence/absence of deafferentation, peripheral or central sensitization, and descending modulation) according to BSTK-PHN findings, though not with a high level of reliability between investigators. Further research in a larger sample is warranted to define a reliable algorithm for classification of PHN patients into subgroups based on sensory profiles. Overall, the BSTK-PHN is a convenient, reliable sensory testing tool for the classification of PHN patients into putative pain mechanism subgroups in PHN clinical trials. This study was supported by Merck. Postherpetic Neuralgia (PHN) is a heterogeneous and complex pain syndrome that involves various pain mechanisms. It is believed that PHN patients could be classified into different sensory profiles using quantitative sensory testing. Because no standardized, comprehensive sensory assessment easily performed at bedside exists for PHN, we developed a Bedside Sensory Testing Kit for PHN (BSTK-PHN) to classify patients with PHN based on presence of peripheral and/or central sensitization. The kit was tested in a usability and informal (not powered) reliability study in 12 PHN patients. Subjects completed a neuropathic pain questionnaire and underwent sensory testing with the BSTK-PHN, which involves measuring (i) static and dynamic mechanical allodynia using a pressure algometer, (ii) punctate hyperalgesia via pinprick, (iii) low-threshold mechanoreceptive function using von Frey filaments; (iv) cold allodynia using a brass rod; (v) wind-up to temporal summation using the von Frey filaments; and (vi) diffuse noxious inhibitory control (DNIC) after heterotopic noxious conditioning stimulation (HNCS) using a pressure algometer. The BSTK-PHN assessments had a highly acceptable level of tolerability and usability for both subjects and investigators. Inter-rater reliability (kappa analysis) was above the pre-specified acceptability threshold for all assessments of the BSTK-PHN (>0.70), except for the DNIC, which was slightly below 0.70. Subjects appeared to cluster into discrete subgroups (based on the presence/absence of deafferentation, peripheral or central sensitization, and descending modulation) according to BSTK-PHN findings, though not with a high level of reliability between investigators. Further research in a larger sample is warranted to define a reliable algorithm for classification of PHN patients into subgroups based on sensory profiles. Overall, the BSTK-PHN is a convenient, reliable sensory testing tool for the classification of PHN patients into putative pain mechanism subgroups in PHN clinical trials. This study was supported by Merck.

Effect of TENS on pain in relation to central sensitization in patients with osteoarthritis of the knee: study protocol of a randomized controlled trial

BackgroundCentral sensitization has recently been documented in patients with knee osteoarthritis (OAk). So far, the presence of central sensitization has not been considered as a confounding factor in studies assessing the pain inhibitory effect of tens on osteoarthritis of the knee. The purpose of this study is to explore the pain inhibitory effect of burst tens in OAk patients and to explore the prognostic value of central sensitization on the pain inhibitory effect of tens in OAk patients.MethodsPatients with knee pain due to OAk will be recruited through advertisements in local media. Temporal summation, before and after a heterotopic noxious conditioning stimulation, will be measured. In addition, pain on a numeric rating score, WOMAC subscores for pain and function and global perceived effect will be assessed. Patients will be randomly allocated to one of two treatment groups (tens, sham tens). Follow-up measurements will be scheduled after a period of 6 and 12 weeks.DiscussionTens influences pain through the electrical stimulation of low-threshold A-beta cutaneous fibers. The responsiveness of central pain-signaling neurons of centrally sensitized OAk patients may be augmented to the input of these electrical stimuli. This would encompass an adverse therapy effect of tens. To increase treatment effectiveness it might be interesting to identify a subgroup of symptomatic OAk patients, i.e., non-sensitized patients, who are likely to benefit from burst tens.Trial RegistrationClinicalTrials.gov: NCT01390285

Abnormal spinal cord pain processing in Huntington’s disease. The role of the diffuse noxious inhibitory control

ObjectivesOur study is aimed to evaluate the spinal cord pain processing in Huntington’s disease (HD) by testing both the temporal summation threshold (TST) of the nociceptive withdrawal reflex (NWR) and the functional activity of the diffuse noxious inhibitory control (DNIC) as form of supraspinal control of pain. MethodsWe enrolled 19 HD patients and 17 healthy controls. We measured threshold (Th), Area, TST and related psychophysical pain sensations of the NWR, at baseline and during and after activation of the DNIC by means of cold pressor test (CPT) as heterotopic noxious conditioning stimulation. ResultsIn HD patients we found a significantly higher Th and TST as well as a lower Area when compared to controls. During the CPT, a significant inhibition of reflex and psychophysical pain responses were found in both HD patients and controls when compared to baseline, without differences between the groups in CPT results. ConclusionsOur study demonstrated an abnormal spinal cord pain processing in HD patients. Abnormalities in pain processing are not apparently linked to a dysfunctional DNIC inhibitory projection system in HD patients. SignificanceOur findings support the hypothesis that the striatum could play a role in pain modulation and that its atrophy could affect pain processing without change the DNIC efficiency.

Treating pain with pain: Supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation

While being exposed to an intensive tonic pain stimulus at one area of the body, another phasic pain stimulus applied to a remote site is perceived as less painful. The neurophysiological basis for this “pain inhibits pain” phenomenon has been presumed to be an activation of the spino-bulbo-spinal mechanism termed “diffuse noxious inhibitory controls.” However, several additional mechanisms such as an activation of the descending pain control system may contribute to this observation. Here we investigated the underlying supraspinal mechanisms of “heterotopic noxious conditioning stimulations” (HNCS), representing this specific experimental constellation. We used functional magnetic resonance imaging and behavioral recordings in combination with a modified cold-pressor task and phasic painful stimuli, and investigated the contribution of endogenous opioids to this mechanism using the opioid antagonist naloxone in a double-blind crossover design. HNCS led to marked endogenous analgesia and this effect correlated positively with the perceived intensity of the tonic painful stimulus. Furthermore, HNCS was paralleled by reduced blood oxygen level dependent (BOLD) responses in classical pain-responsive regions. Conversely, HNCS led to tonic BOLD increases in subregions of the anterior cingulate cortex. The strength of functional coupling between the subgenual anterior cingulate cortex and key structures of the descending pain control system was enhanced during HNCS, which correlated positively with the individual endogenous analgesia during HNCS. These effects were in part reversed by naloxone, speaking for the contribution of endogenous opioid neurotransmission to this mechanism. Taken together, these results demonstrate a substantial contribution of higher-order brain regions to the phenomenon of hypoalgesia during HNCS.Functional magnetic resonance imaging shows how the human brain is involved in heterotopic noxious conditioning and reveals active supraspinal pain modulatory mechanisms during dual pain stimulation.

A psychophysical study of endogenous analgesia: The role of the conditioning pain in the induction and magnitude of conditioned pain modulation

Endogenous analgesia (EA) can be examined experimentally using a conditioned pain modulation (CPM) paradigm. While noxious conditioning stimulation intensities (CSIs) are mainly used, it has not been fully investigated in the same experimental design whether the experienced conditioning pain level affects CPM responses. The principal goal of the present study was to characterize CPM induction and magnitudes evoked by various conditioning pain levels. Furthermore, we explored associations between conditioning pain reports and CPM responses across various CSIs. Thirty healthy, young, right-handed males were tested with a parallel CPM paradigm. Three different CSIs (hand water-immersion) induced mild, moderate and intense pain levels, rated 12.41 ± 7.85, 31.57 ± 9.56 and 58.1 ± 11.43, respectively (0–100 numerical pain scale) ( P < 0.0001). Contact-heat ‘test-stimulus’ levels were compared before and during conditioning. Within the group, (i) CPM was induced only by the moderate and intense CSIs ( Ps ⩽ 0.001); (ii) no difference was demonstrated between the magnitudes of these CPM responses. Regression analysis revealed that CPM induction was independent of the perceived conditioning pain level, but associated with the absolute CSI ( P < 0.0001). Conditioning pain levels were correlated across all CSIs, as were CPM magnitudes ( Ps ⩽ 0.01). We conclude that among males, (i) once a CPM response is evoked by a required conditioning pain experience, its magnitude is not further affected by increasing conditioning pain and (ii) CPM magnitudes are inter-correlated, but unrelated to conditioning pain reports. These observations may suggest that CPM responses represent an intrinsic element of an individual’s EA processes, which are not significantly affected by the experienced conditioning pain.

Heterotopic pruritic conditioning and itch – Analogous to DNIC in pain?

Pain can be endogenously modulated by heterotopic noxious conditioning stimulation (HNCS) through a mechanism which is known as diffuse noxious inhibitory control (DNIC). Since DNIC can be impaired in patients suffering from chronic pain, a comparable impaired itch inhibition may exist in patients suffering from chronic itch. The aim of the present study was to investigate whether heterotopic pruritic conditioning stimulation (HPCS) would display an impaired modulation of itch in patients suffering from chronic itch compared with healthy subjects. To this end, electrical stimuli were applied before and after histamine application (HPCS) to female patients with psoriasis and healthy female control subjects. Subjects reported the intensity of electrically evoked itch before and after HPCS. In order to replicate earlier findings for DNIC, electrically evoked pain was additionally investigated before and after cold stimulation (HNCS). As expected, the intensity of itch evoked by the electrical stimulus was significantly less after than before HPCS in healthy subjects, and the same was found for the intensity of electrically evoked pain after compared to before HNCS. Contrarily, in the patients levels of electrically evoked itch were significantly higher after than before HPCS, and no significant difference in pain intensity before and after HNCS was observed. In line with pain modulation, results suggest that there is a DNIC analogous mechanism for itch, i.e., diffuse pruritic inhibitory control (DPIC), which is impaired in patients with chronic itch, possibly due to a dysregulation of descending itch modulatory systems.

Influence of heterotopic noxious conditioning stimulation on spontaneous pain and dynamic mechanical allodynia in central post-stroke pain patients

In 10 patients with central post-stroke pain (CPSP), the influence of ischemia-induced heterotopic noxious conditioning stimulation (HNCS) on the intensity of spontaneous ongoing- and brush-evoked pain was examined. In addition, the modulating effect of ongoing pain and HNCS on pain sensitivity in a remote pain-free area was explored. A semi-quantitative brushing technique was employed in combination with a computerized visual analogue scale (VAS) to monitor the allodynic percept over time, by calculating the area under the VAS curve as the total brush-evoked pain intensity. Heat- and pressure pain thresholds and sensitivity to suprathreshold heat- and pressure pain in the pain-free area were assessed before and during HNCS. No significant alterations of ongoing- or brush-evoked pain were found during HNCS, although 6 of 10 patients rated a reduction of about 50% of the brush-evoked pain. At baseline significantly increased pressure pain sensitivity (threshold P < 0.05; suprathreshold P = 0.05) were demonstrated in patients compared to controls. During HNCS, higher pressure pain thresholds were demonstrated in patients and controls alike ( P < 0.001), whereas in controls only decreased sensitivity to suprathreshold pressure pain was found ( P < 0.05). Lack of influence from HNCS on ongoing- and brush-evoked pain on a group level, indicates inability of modulation from endogenous pain controlling systems on nociceptive activity generated in the brain. Increased pressure pain sensitivity at baseline suggests alteration in corticofugal control of nociceptive sensitivity due to the brain lesion, whereas patients during HNCS seemed to activate modulatory systems interacting with nociceptive input from the spinal level equal to controls.