Thermal pain thresholds are decreased in the migraine preattack phase

Background and purpose: Migraine patients may have cutaneous allodynia during attacks. In order to investigate if pain physiology changes in the preattack phase we estimated heat pain and cold pain detection threshold (HPT and CPT) on three different days in 41 migraine patients and 28 controls. Methods: A thermode was applied at four sites bilaterally: forehead, face, neck, and hand. A subgroup of 11 migraine patients had been tested within 24 h before their next attack and in the interictal phase. Results: In the preattack phase, HPT was lower compared with the paired interictal recording for the hand (44.8°C vs. 45.9°C, P = 0.009), neck (46.8°C vs. 48.2°C, P = 0.02), and forehead (45.1°C vs. 46.3°C, P = 0.02). Neck and hand CPT were higher in the preattack phase than interictally (10°C vs. 7.3°C, P = 0.01 and 11.6°C vs. 9.4°C, P = 0.06, respectively). Preattack forehead changes were most apparent on the headache side of the subsequent attack. Discussion: Subclinical preattack thermal pain hypersensitivity seems to be a feature of the process that leads to a migraine attack.     

Influence of age on rectal tone and sensitivity to distension in healthy subjects

Hypersensitivity to rectal distension is frequently observed in patients with irritable bowel syndrome (IBS). However, few data are available about the influence of age on rectal sensory thresholds and tone. The aim of this study was to measure rectal sensory thresholds and tone with a barostat in 12 healthy subjects (aged 86 +/- 4 years, eight females, four males) as compared with 12 young healthy male controls (26 +/- 1 years). Isobaric phasic distensions were performed in the fasted state (increment of 4 mmHg, steps of 5 min, interval of 5 min). Rectal tone changes were then measured as changes in volume of the barostat bag, the pressure being kept constant. After a baseline recording of 1 h, a 1000-kcal meal was served and the tone recorded until return to baseline. Rectal sensory thresholds were significantly higher in aged subjects. First sensation, sensation of urge to defaecate and sensation of pain were triggered at 21.1 +/- 3.2 mmHg, 30.4 +/- 5.4 mmHg and 40.5 +/- 5.0 mmHg, respectively, in aged subjects, vs 13.3 +/- 4.6 mmHg (P < 0.05), 20.7 +/- 1.0 mmHg (P < 0.001) 31.3 +/- 1.7 mmHg (P < 0.001) in controls. Rectal compliance was not significantly different between the two groups. Mean barostat bag volume was 104 +/- 13 mL in fasting aged subjects and 125 +/- 23 mL in controls (NS). After the meal, the barostat bag volume decreased by 69 +/- 11% during 85 +/- 17 min in aged subjects and 75 +/- 14% during 89 +/- 15 min in young controls (NS). Rectal sensory thresholds triggered by distension are increased in aged healthy subjects while compliance and tone are not different. Age should be considered as a confounding factor when studying rectal sensitivity and further studies in aged patients with IBS should include a group of control subjects within the same range of age as studied patients.     

Sympathetic (electrodermal) activity during repeated maximal rectal distensions in patients with irritable bowel syndrome and constipation

Abstract  Irritable bowel syndrome (IBS) is associated with visceral hypersensitivity, stress and autonomic dysfunction. Sympathetic activity during repeated events indicates excitatory or inhibitory mechanisms such as sensitization or habituation. We investigated skin conductance (SC) during repetitive rectal distensions at maximal tolerable pressure in patients with IBS and chronic constipation. Twenty-seven IBS patients, 13 constipation patients and 18 controls underwent two sets of isobaric rectal distensions. First, maximal tolerable distension was determined and then it was repeated five times. Skin conductance was measured continuously. Subjective symptom assessment remained steady in all groups. The baseline values of SC were higher in IBS patients than in patients with constipation and significantly lower in constipation patients than in controls. The maximal SC response to repetitive maximal distensions was higher in IBS patients compared with constipation patients. The amplitude of the initial SC response decreased successively with increased number of distensions in patients with IBS and constipation but not in controls. Irritable bowel syndrome and constipation patients habituated to maximal repetitive rectal distensions with decreasing sympathetic activity. Irritable bowel syndrome patients had higher sympathetic reactivity and baseline activity than constipation patients. A lower basal SC in constipation patients compared with controls suggests an inhibition of the sympathetic drive in constipation patients.     

Neuronal correlates of gastric pain induced by fundus distension: a 3T-fMRI study

Visceral hypersensitivity in gastric fundus is a possible pathogenesis for functional dyspepsia. The cortical representation of gastric fundus is still unclear. Growing evidence shows that the insula, but not the primary or secondary somatosensory region (SI or SII), may be the cortical target for visceral pain. Animal studies have also demonstrated that amygdala plays an important role in processing visceral pain. We used fMRI to study central projection of stomach pain from fundus balloon distension. We also tested the hypothesis that there will be neither S1 nor S2 activation, but amygdala activation with the fundus distension. A 3T-fMRI was performed on 10 healthy subjects during baseline, fullness (12.7 +/- 0.6 mmHg) and moderate gastric pain (17.0 +/- 0.8 mmHg). fMRI signal was modelled by convolving the predetermined psychophysical response. Statistical comparisons were performed between conditions on a group level. Gastric pain activated a wide range of cortical and subcortical structures, including thalamus and insula, anterior and posterior cingulate cortices, basal ganglia, caudate nuclei, amygdala, brain stem, cerebellum and prefrontal cortex (P < 0.001). A subset of these neuronal substrates was engaged in the central processing of fullness sensation. SI and SII were not activated during the fundus stimulation. In conclusion, the constellation of neuronal structures activated by fundus distension overlaps the pain matrices induced musculocutaneous pain, with the exception of the absence of SI or SII activation. This may account for the vague nature of visceral sensation/pain. Our data also confirms that the insula and amygdala may act as the central role in visceral sensation/pain, as well as in the proposed sensory-limbic model of learning and memory of pain.     

Common neural systems for contact heat and laser pain stimulation reveal higher-level pain processing

Our current knowledge of pain-related neuronal responses is largely based on experimental pain studies using contact heat or nontactile laser painful stimulation. Both stimuli evoke pain, yet they differ considerably in their physical and perceptual properties. In sensory cortex, cerebral responses to either stimulus should therefore substantially differ. However, given that both stimuli evoke pain, we hypothesized that at a certain subset of cortical regions the different physical properties of the stimuli become less important and are therefore activated by both stimuli. In contrast, regions with clearly dissociable activity may belong to "lower-level" pain processing mechanisms depending on the physical properties of the administered stimuli. We used functional magnetic resonance (fMRI) to intraindividually compare pain-related activation patterns between laser and contact heat stimulation using four different intensities of laser and contact heat stimuli. Common and dissociable neural responses were identified by correlating perceived pain intensities with blood oxygenation level dependent (BOLD) signal changes. Only neuronal responses to stimuli that were perceived as painful were analyzed. Pain-related BOLD signal increases independent of stimulus modality were detected in the anterior insula, anterior cingulate cortex, medial secondary somatosensory cortex, and the prefrontal cortex. These similarities are likely to reflect higher-level pain processing, which is largely independent of the single physical parameters that determine the painful nature of the stimuli.     

Attentional modulation of visceral and somatic pain

A better understanding of the cortical processes underlying attentional modulation of visceral and somatic pain in health are essential for interpretation of future imaging studies of hypervigilance towards bodily sensations which is considered to be an aetiologically important factor in the heightened pain reported by patients with irritable bowel syndrome and fibromyalgia. Twelve healthy subjects were recruited for this study. Simultaneous trains of electrical pulses (delivered to either the rectum or lower abdomen) and auditory tones lasting 6 s were delivered to the subjects during a whole-brain functional scan acquisition. Subjects were instructed to attend to the auditory tones (distracter task) or electrical pulses (pain task). Pain intensity ratings were significantly lower during the distraction task compared with the pain task (P < 0.01) in both sensory modalities. The left primary somatosensory cortex increased in activity with increasing pain report, during attention to visceral pain. Bilateral anterior insula (aIns) cortex activity increased with increasing somatic pain report independent of the direction of attention. Conversely, the primary and secondary auditory cortices significantly increased in activation with decreased pain report. These results suggest that pain intensity perception during attentional modulation is reflected in the primary somatosensory cortex (visceral pain) and aIns cortex activity (somatic pain).     

Ventral posterolateral deep brain stimulation treatment for neuropathic pain shortens pain response after cold stimuli

Neuropathic pain is often severe. Deep brain stimulation (DBS) is a treatment method for neuropathic pain, but its mechanism of action remains unclear. Patients with neuropathic pain are affected by various stimulations, such as mechanical and cold stimuli, but studies of cold allodynia showed the associated pain to be less than that caused by mechanical stimuli. This study focused on the effects of DBS on cold allodynia in rats. To observe the effects of DBS, we established three groups: a normal group (normal), a neuropathic pain group (pain), and a DBS with neuropathic pain group (DBS). The stimulation target was the ventral posterolateral nucleus (VPL). We observed differences in the degree of cold allodynia elicited between a conventional method that measured the number of pain responses and our altered novel method that measured the duration of pain responses. Cold allodynia after DBS did not differ when conventional analysis was applied, but the pain response duration was decreased. We suggest that VPL DBS was partially effective in cold allodynia, implicating complex pathways of pain signaling. © 2013 Wiley Periodicals, Inc.     

Side-to-side differences in pressure pain thresholds and pericranial muscle tenderness in strictly unilateral migraine

Previous studies dealing with pressure pain sensitivity or muscle tenderness in migraine have shown conflicting results. Our aim was to explore the differences in mechanical pain sensitivity and pericranial muscle tenderness between patients with unilateral migraine and healthy controls, and to analyse side‐to‐side differences in both study groups. Pressure pain thresholds (PPT) at cephalic and neck points, plus local and total tenderness scores were blindly assessed in 25 patients with strictly unilateral migraine and 25 healthy subjects. For PPT in the neck there were significant differences between groups (F = 47.029; P < 0.001) and sides (F = 6.363; P < 0.01), and a significant interaction between group and side (F = 5.201; P = 0.02), while PPT in the cephalic point showed differences between groups (F = 11.774; P < 0.001), but not sides (F = 2.838; P = 0.1). The total tenderness score showed significant differences between groups (F = 6.800; P < 0.01) and sides (F = 17.699; P < 0.001), along with a significant interaction between group and side (F = 14.420; P < 0.001). Patients had lower PPT and increased pericranial tenderness on the symptomatic side as compared with the non‐symptomatic side and to either side in controls (P < 0.001), whereas no significant differences were identified between the non‐symptomatic side and controls (P > 0.9). In migraine patients, PPT levels and muscle tenderness scores were negatively correlated (P < 0.001). The enhancement of local tenderness scores was related to hyperesthesia of specific muscles (sternocleidomastoid, suboccipital, and temporalis) rather than a generalized pericranial tenderness. Future studies should investigate the neuro‐physiological basis for the laterality of allodynic and hyperalgesic responses in unilateral migraine.     

Association of Serum Total Antioxidant Capacity and Total Oxidant Status with Pain Perception in Patients with Myofacial pain Dysfunction

We aimed to find out the association of total antioxidant capacity (TAC) and total oxidant status (TOS) with generalized pressure pain thresholds (PPT) of patients with myofacial pain dysfunction (MPD). PPT scores of patients with MPD (n = 37) and healthy individuals (n = 43) were measured on the hypothenar region of the hand using a mechanical algometer. Serum samples were collected and TAC and TOS were measured by novel methods. The TAC of patients was significantly lower than that of the control subjects. The difference between the TOS measurements of patients and control subjects was not significant. The PPT scores of the patients were significantly lower than that of control subjects. There may be an association between serum antioxidant capacity and MPD. Low serum TAC might also be related with pain perception.     

The d-alanine content of lipoteichoic acid is crucial for Lactobacillus plantarum-mediated protection from visceral pain perception in a rat colorectal distension model

Abstract  The mechanisms leading to positive effects of probiotics in irritable bowel syndrome and inflammatory bowel disease have not been clarified, but the possible involvement of cell wall components is widely discussed. Reduction of the d -alanine content of lipoteichoic acid (LTA) in Lactobacillus plantarum (Dlt ⁻ mutant) enhanced its anti-inflammatory properties in a mouse colitis model. Another lactobacillus species inhibited visceral pain perception in response to colorectal distension (CRD) in rats. Therefore, we investigated if LTA modification influences the constitutive intestinal pain perception in addition to modulation of cytokine release. Male Sprague-Dawley rats were gavaged with L. plantarum , L. plantarum Dlt ⁻ mutant or buffer control, respectively and the responses to CRD were tested in this non-inflammatory model. Tumour necrosis factor (TNF), interferon (IFN)-gamma and interleukin (IL)-10 release were measured in colon tissue homogenates and upon anti-CD3/CD28 activation of isolated splenocytes and mesenteric lymphocytes. Control animals showed significant bradycardia following noxious CRD, whereas only the L. plantarum Dlt ⁻ mutant inhibited the response. The mutant also decreased the activation-induced release of TNF and IFN-gamma from mesenteric T cells and the IL-10 concentration in colonic tissue, while increasing the activation-induced secretion of IL-10 in splenocytes and mesenteric lymphocytes and the baseline IL-10 release of splenocytes. In conclusion, d -alanine depletion of LTA in L. plantarum inhibited visceral pain perception in healthy, non-inflamed rats. Regardless of the non-inflammatory nature of the model decreased visceral pain perception was seen in parallel with anti-inflammatory properties.     

Influence of intrinsic noise generated by a thermotesting device on thermal sensory detection and thermal pain detection thresholds

Various factors can influence thermal perception threshold measurements and contribute significantly to unwanted variability of the tests. To minimize this variability, testing should be performed under strictly controlled conditions. Identifying the factors that increase the variability and eliminating their influence should increase reliability and reproducibility. Currently available thermotesting devices use a water‐cooling system that generates a continuous noise of approximately 60 dB. In order to analyze whether this noise could influence the thermal threshold measurements we compared the thresholds obtained with a silent thermotesting device to those obtained with a commercially available device. The subjects were tested with one randomly chosen device on 1 day and with the other device 7 days later. At each session, heat, heat pain, cold, and cold pain thresholds were determined with three measurements. Bland–Altman analysis was used to assess agreement in measurements obtained with different devices and it was shown that the intersubject variability of the thresholds obtained with the two devices was comparable for all four thresholds tested. In contrast, the intrasubject variability of the thresholds for heat, heat pain, and cold pain detection was significantly lower with the silent device. Our results show that thermal sensory thresholds measured with the two devices are comparable. However, our data suggest that, for studies with repeated measurements on the same subjects, a silent thermotesting device may allow detection of smaller differences in the treatment effects and/or may permit the use of a smaller number of tested subjects. Muscle Nerve 40: 257–263, 2009     

Activation of lumbar spinoreticular neurons by stimulation of muscle, cutaneous and sympathetic afferents

Forty-four spinal neurons located mainly in laminae IV–VII of the L7 and S1 segments projected primarily contralaterally and to the lateral reticular nucleus. Muscle and cutaneous input was via group II and III afferents, whereas sympathetic input was via group III or IV afferents. Close-arterial injection of bradykinin and/or caosaicin excited most of the neurons so tested. These responses make these neurons likely candidates for the ascending pathway of the exercise pressor reflex.     

Chronic pain has a small influence and mood has no influence on vibrotactile perception thresholds among working women

In chronic diffuse upper limb pain physical abnormalities are usually absent. The aims of our study were to investigate: (1) the function of somatosensory pathways and (2) the influence of mood on vibration perception. Measurements were made of: (i) vibrotactile perception thresholds (VPTs) and nerve conduction in working women with (n = 35) and without (n = 65) chronic diffuse upper limb pain, and (ii) perceived stress and energy using a two‐dimensional mood adjective checklist. The groups did not differ in any nerve conduction measurements. Women with chronic pain had raised VPTs in the radial and ulnar nerve areas, but not in the median nerve area. Neither perceived stress nor energy appeared to influence the VPT. Increases of VPTs in chronic diffuse upper limb pain may be due to peripheral nerve affliction, but our findings support the idea that they may also be secondary to pain and may be related to a central nervous mechanism. Muscle Nerve, 2010     

Inhibitory effect of voluntary movement preparation on cutaneous heat pain and laser-evoked potentials

In our study, preparation of voluntary movement was used to physiologically activate the motor cortex areas and the effect of this activation on CO(2) laser-evoked potentials (LEPs) was explored. LEPs were recorded from 31 scalp electrodes in 10 healthy subjects after painful stimulation of the right C6-C7 skin dermatomes. LEP stimuli were delivered in the time interval between a visual warning stimulus followed after 1 s. by an imperative stimulus. The imperative stimulus triggered: (i) no task in the baseline condition (Pain); (ii) flexion-extension movements of the second finger of the right hand in the movement condition (Pain + Movement); (iii) cognitive task (mathematic computation) in the distraction condition (Pain + Cognition). The experimental conditions were also repeated during application of laser stimuli on the left C6-C7 skin dermatomes. Compared with the baseline condition (no task required), during preparation of right-hand voluntary movement there was a significant reduction in LEP amplitude and subjective pain rating after right- but not after left-hand stimulation, which suggests that the observed effect cannot be attributed to a nonspecific reduction in attention toward painful stimulus. During preparation of a cognitive task, LEP amplitude was reduced compared to baseline. Our results represent the first neurophysiological suggestion that physiological activation of the motor cortex, occurring during movement preparation, inhibits cortical pain processing by a centrifugal mechanism.     

Age changes in pain perception: A systematic-review and meta-analysis of age effects on pain and tolerance thresholds

Demographic changes, with substantial increase in life expectancy, ask for solid knowledge about how pain perception might be altered by aging. Although psychophysical studies on age-related changes in pain perception have been conducted over more than 70 years, meta-analyses are still missing. The present meta-analysis aimed to quantify evidence on age-related changes in pain perception, indexed by pain thresholds and pain tolerance thresholds in young and older healthy adults. After searching PubMed, Google Scholar and PsycINFO using state-of-art screening (PRISMA-criteria), 31 studies on pain threshold and 9 studies assessing pain tolerance threshold were identified. Pain threshold increases with age, which is indicated by a large effect size. This age-related change increases the wider the age-gap between groups; and is especially prominent when heat is used and when stimuli are applied to the head. In contrast, pain tolerance thresholds did not show substantial age-related changes. Thus, after many years of investigating age-related changes in pain perception, we only have firm evidence that aging reduces pain sensitivity for lower pain intensities.     

How positive and negative expectations shape the experience of visceral pain: an experimental pilot study in healthy women

Background In order to elucidate placebo and nocebo effects in visceral pain, we analyzed the effects of positive and negative expectations on rectal pain perception, rectal pain thresholds, state anxiety and cortisol responses in healthy women. Methods Painful rectal distensions were delivered at baseline, following application of an inert substance combined with either positive instructions of pain relief (placebo group, N = 15), negative instructions of pain increase (nocebo group, N = 17), or neutral instructions (control, N = 15). Perceived pain intensity, unpleasantness/aversion and urge‐to‐defecate, state anxiety and serum cortisol were determined at baseline, immediately following group‐specific instructions and on a second study day after the same instructions (test day). Rectal pain thresholds were determined at baseline and on the test day. Key Results Whereas perceived pain intensity was significantly decreased in the placebo group, the nocebo group revealed significantly increased pain intensity ratings, along with significantly greater anticipatory anxiety on the test day (all P < 0.05 vs controls). Cortisol concentrations were significantly increased in the nocebo group following treatment but not on the test day. Conclusions & Inferences The experience of abdominal pain can be experimentally increased or decreased by inducing positive or negative expectations. Nocebo effects involve a psychological stress response, characterized by increased anticipatory anxiety. These findings further underscore the role of cognitive and emotional factors in the experience of visceral pain, which has implications for the pathophysiology and treatment of patients with chronic abdominal complaints.