Conditioned pain modulation

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Current methodological approaches in conditioned pain modulation assessment in pediatrics

Current methodological approaches in conditioned pain modulation assessment in pediatrics

No significant differences in CPM among groups. Authors comment on age effects and consider separating groups by teenage vs childhood years. Pain anxiety and catastrophizing are predictive of greater pain morbidity and pain sensitivity, respectively Abbreviations: CPM, conditioned pain modulation; TS, test stimulus; CS, conditioning stimulus; NICU, neonatal intensive care unit; CPT, cold pressor task; pain rating, based on self-reported score; IBS, Irritable bowel syndrome; FAP, functional abdominal pain; PFP, patellofemoral pain; MSK pain, musculoskeletal pain; EIH, exercise-induced hypoalgesia.
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Evoked potentials after painful cutaneous electrical stimulation depict pain relief during a conditioned pain modulation

Evoked potentials after painful cutaneous electrical stimulation depict pain relief during a conditioned pain modulation

After approval by the local ethics committee (Reg. Nr. 15–5300; 06–16-2015) 18 healthy subjects (age > 18 years) were recruited after informed consent, using recently recommended inclusion and exclusion criteria [34]. The study was conducted in the department of Neurology, University Hospital Bergmannsheil Bochum, Germany between June and August 2015. Exclusion criteria in- cluded current pain, neuropathy, nerve lesions, topical drug treatment, history of neurological, psychiatric or severe cardiovascular diseases. A sample size calcula- tion was performed using data on changes of the N2- P2-amplitudes of contact heat evoked potentials (CHEP) from a study examining the conditioned pain modulation with CHEP as a test stimulus and painful heat as conditioning stimulus [2] and revealed for a power of 80%, type I error of 0.05 and an estimated drop-out rate of 5% a sample size of at least 14 subjects per study arm in a crossover design.
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Expectations of increased and decreased pain explain the effect of conditioned pain modulation in females

Expectations of increased and decreased pain explain the effect of conditioned pain modulation in females

Objective: Chronic pain is believed to be related to a dysfunction of descending pain modulatory mechanisms. Functioning of descending pain modulation can be assessed by various methods, including conditioned pain modulation (CPM). CPM refers to the inhibition of one source of pain by a second noxious stimulus, termed the conditioning stimulus. This procedure can activate an endogenous pain inhibitory mechanism that inhibits early nociceptive processing. Chronic pain and anxiety disorders are more prevalent among females and it has been hypothesized that females react with more negative emotions towards unpleasant stimuli and this might be part of the explanation of greater pain sensitivity in females. The present study investigated whether expectations modulate the effect of conditioning stimulation on pain, subjective stress, and heart rate. In addition, we investigated whether the modulation of CPM by expectations differed between males and females.
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The effects of a conditioning stimulus provided as cold pressor test on the conditioned pain modulation of healthy persons based on the subjective experience of pain

The effects of a conditioning stimulus provided as cold pressor test on the conditioned pain modulation of healthy persons based on the subjective experience of pain

Multireceptive neurons in the dorsal horn and the trigeminal nuclei caudalis and oralis are found in both superficial and deeper layers of lamina V. They receive input from primary nociceptive neurons and non- nociceptive neurons. Multireceptive neurons are also called ”wide-dynamic range” (WDR), ”convergent”, ”lamina V type” or ”class 2” neurons. These interneurons are involved in sending information to ascending pathways and to polysynaptic reflexes. A conditioning noxious stimulation of various areas of the body (unrelated to the receptive fields of the multireceptive neurons) can inhibit the activity of multireceptive neurons. This causes activation of the descending inhibitory mechanisms, which decreases pain responses to a second stimulus. Inhibition of one stimulus by the perception of a second stimulus, is called pain- inhibits-pain counterirritation. The pain relieving effect of counterirritation is provided by the ”Diffuse Noxious Inhibitory Controls” (DNIC) mechanism. Only ”noxious” is used in the term ”DNIC” since it was originally thought that noxious stimuli could only inhibit second noxious stimuli. However, later studies suggested that non-noxious conditioning stimuli could also induce DNIC to some extent. Therefore the new term Conditioned Pain Modulation (CPM) was given. Thus according to those studies, multireceptive neurons are also activated by non-noxious stimuli.[21][22][23][24]
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<p>Racial differences in experimental pain sensitivity and conditioned pain modulation: a study of Chinese and Indians</p>

<p>Racial differences in experimental pain sensitivity and conditioned pain modulation: a study of Chinese and Indians</p>

Pain is considered to be an experience with sensory, cognitive and emotional components. 1 Besides the biological basis of pain, cultural and social factors are also viewed as the foundation to the expression and treatment of pain. 2 Race is a social categorization imposed on people related to physical appearance for the purpose of making hierarchical power-based distinctions in social relations. 3 Experimental pain testing in healthy individuals helps to elucidate potential differences in pain perception, without being confounded by disease-speci fi c factors and disparities in pain management present in clinical pain studies. 4,5 Racial disparities in pain perception and response have been demonstrated, with most of the research conducted on African-Americans and Caucasians. 6,7 African-Americans exhibit lower pain tolerance and higher unpleasant- ness ratings than Caucasians in experimental pain studies. 6,7 Several studies have compared Caucasians with Asians such as Indian and Chinese. 8–12 Asians generally demonstrated lower pain tolerances than Caucasians. 11,12 The evidence for lower pain
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Stability of conditioned pain modulation in two musculoskeletal pain models: investigating the influence of shoulder pain intensity and gender

Stability of conditioned pain modulation in two musculoskeletal pain models: investigating the influence of shoulder pain intensity and gender

Previous studies investigating endogenous pain modula- tion in chronic pain populations have shown a potential deficiency of pain inhibitory system [3,6,7,10,12,26,50,55]. It has also been shown that CPM could be a predictor for post operative pain and potentially sensitive to changes in the central nervous system [3,50]. However, since CPM is a proxy measure of central pain inhibitory process, t, it is particularly important to estimate the error associated with this commonly used measure in order to be useful in research and clinical decision making. After performing a reliability analysis in these two cohorts and establishing that CPM is a measure moderately stable independent of changes in pain intensity, we are in a better stage to use this measure in clinical settings (from a reliability stand point). If we think that CPM is a proxy measure of central pain inhibitory system, with a moderate reliability we may speculate that higher stability may be expected when assessing a population with chronic pain (which may have less variability in central sensitization), however future studies need to be performed to test this hypothesis.
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Conditioned pain modulation in drug-naïve patients with de novo Parkinson’s disease

Conditioned pain modulation in drug-naïve patients with de novo Parkinson’s disease

23, 35]. Furthermore, over-night withdrawal of medica- tion had no effect on CPM responses in PD patients [22, 23]. However, this washout phase might have been too short to sufficiently eliminate the dopaminergic medica- tion. Although the plasma half-life period of dopamine agonists is relatively short (usually several hours) [7] and that of levodopa is generally estimated as 0.7 to 1.4 h [11], the latter can last up to 7.9 days [15]. The residual dopaminergic concentration might therefore still have induced antinociceptive effects [4] and could have nor- malized a reduced CPM response in PD patients. A re- cent study in patients with restless leg syndrome suggested that antinociceptive/analgesic effects of dopa- mine are concentration-dependent [4]. Low dopamin- ergic concentrations induced antinociceptive effects via dopaminergic D2 receptors, whereas higher levels had pro-nociceptive effects based on the activation of D1 re- ceptors [4, 40]. Dopamine could therefore either in- crease or decrease CPM responses in PD patients depending on its concentration and low concentra- tions might have led to decreased pain during the in- sufficient washout phase.
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Sex differences in the relationship between maternal fear of pain and children&#39;s conditioned pain modulation

Sex differences in the relationship between maternal fear of pain and children&#39;s conditioned pain modulation

Pain intensity was assessed immediately following each administration of the test stimulus; participants rated the highest level of pain during the trial using the NRS. Anticipatory anxiety was assessed prior to the CPM task and was rated on the NRS. Participants were asked how nervous, afraid, or worried they felt about the upcoming task. Pain-related fear was assessed immediately after the end of the CPM task using the NRS. Participants were asked, at its worst, how nervous, afraid, or worried they felt during the task. The magnitude of CPM was calculated as a difference score between TS1 and TS2. Data for TS3 and TS4 are reported elsewhere. 22 More negative values for the
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Conditioned pain modulation is minimally influenced by cognitive evaluation or imagery of the conditioning stimulus

Conditioned pain modulation is minimally influenced by cognitive evaluation or imagery of the conditioning stimulus

Our pilot study has two limitations. First, our sample size is limited. Although our study has enough power to replicate previous results of both the standard cold water CPM task and the evaluation task, we did not detect any effects of evalu- ation or imagery. We estimate that we would need to triple our sample size to have adequate power to detect the possible effects of imagery, and more than quadruple our sample size to detect the possible effect of evaluation. However, even if our results nonetheless indicate whether imagery and evaluation can affect CPM, the magnitude of their effect is much smaller than that seen using a standard cold water conditioning stimulus. This supports the robustness of the standard CPM protocol against cognitive influences. Second, although we randomized the order of evaluations and the second imagery task (and accounted for order in the analysis), order might still have influenced our results. Repeated cold water exposure from the initial thresholding test and the standard CPM task may subsequently decrease the pain ratings from the heat stimulus, because some studies show that CPM may last longer than 5 minutes. 33,34 The actual effect of evaluation and
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Variability in conditioned pain modulation predicts response to NSAID treatment in patients with knee osteoarthritis

Variability in conditioned pain modulation predicts response to NSAID treatment in patients with knee osteoarthritis

Prior studies have hinted at the neurochemical systems that may be involved in mediating CPM and temporal summation [10, 29, 30]. CPM, a sensitive measure of deficits in pain modulation in fibromyalgia and related persistent pain disorders, appears to depend on systems that interact with serotonergic and noradrenergic de- scending inhibitory pathways [31]. Temporal summation, an analog of central sensitization, represents an important pathophysiological process that contributes to the devel- opment and maintenance of pain states in a number of clinical contexts. While the temporal summation of pain involves processes at the spinal level, recent functional neuroimaging studies have highlighted the clear contribu- tion of supraspinal processes as well [32, 33]. Collectively, the modulation of temporal summation appears to involve the activity of descending pain-inhibitory systems, which are known to play crucial roles in pain processing. In prior studies, medications such as NMDA antagonists, GABA agonists, and opioids have all been shown to reduce tem- poral summation of pain [34, 35]. Thus, the amplification of pain sensitivity in this sample of OA patients may reflect the activity of multiple neuroanatomical and neurochemical systems.
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Short-term test-retest-reliability of conditioned pain modulation using the cold-heat-pain method in healthy subjects and its correlation to parameters of standardized quantitative sensory testing

Short-term test-retest-reliability of conditioned pain modulation using the cold-heat-pain method in healthy subjects and its correlation to parameters of standardized quantitative sensory testing

So far, nine studies have been published analysing the test-retest reliability of different CPM paradigms, than the one we used [10–18]. Three of them analysed the re- liability in chronic pain patients or in an experimental pain model for acute musculoskeletal pain [13, 14, 18]. The remaining six studies analysed the test-retest- reliability in healthy subjects using the nociceptive with- drawal reflex (NWR), electric, pressure or heat pain as TS and cold- or hot-water baths and ischemia as CS. Three studies reported similar ICC as in our study ran- ging between 0.54 and 0.69 [10, 11, 15]. However, two studies reported insufficient reliability based on ICC: Biurrun et al. used NWR thresholds, electrical pain thresholds and suprathreshold electrical pain as TS and cold-water bath as CS with ICC of 0.09 to 0.44 within 1–3 weeks for suprathreshold electrical pain [12]. An- other study in healthy females used heat both as TS and CS and achieved ICC = 0.39 for retests over a period of 7–10 months [16]. In contrast, our study concentrated on the short-term test-retest-reliability, which might explain the better ICC, pointing to a more stable CPM-effect over shorter periods of time. Choosing an ap- propriate time period for reassessment is an important as- pect. While re-assessment over very short time periods of 60 min or less [Cathcard2009; Lewis2012] might be more reliable, very short time periods might be insufficient to expect a real treatment effect when examining e.g. changes in the CPM-effect due to an intervention. On the other hand longer time periods between reassessments implicate changed external conditions which might influ- ence the results, especially when examining patients, also Table 4 Correlational analyses between CPM effects and QST parameters at day 1 and day 2
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A novel paradigm to evaluate conditioned pain modulation in fibromyalgia

A novel paradigm to evaluate conditioned pain modulation in fibromyalgia

participated. A clinical pain score rated ≥ 40 on a 100 mm visual analog scale (with 0 = no pain and 100 = worst possible pain) was required for enrollment. Fourteen age-matched (40.3 ± 12.0 years, range: 20–60) female healthy control subjects were also recruited. All subjects provided a medical history and underwent physical examination to screen for concurrent illnesses. Exclusion criteria consisted of signifi- cant medical and psychiatric comorbidities, including morbid obesity, substance abuse within 2 years (including cannabis), cardiovascular disease, lung disease, major depression, and schizophrenia, and current use of opioid analgesics. Other medications for depression, anxiety, and pain were permitted in the FM group as long as stable dosages were maintained during the course of the study. The protocol was approved by the University of Michigan Institutional Review Board, and all subjects gave written consent prior to participation.
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Detecting the neuropathic pain component in the clinical setting: a study protocol for validation of screening instruments for the presence of a neuropathic pain component

Detecting the neuropathic pain component in the clinical setting: a study protocol for validation of screening instruments for the presence of a neuropathic pain component

will be read to the patient from an instruction sheet. Pres- sure Pain Thresholds (PPT) will be tested by use of an pressure algometer (Somedic sales AB, Hörby, Sweden). PPT will be measured on the left and right bodyside once at each location: Thenar (middle part), musculus trapezius pars median (middle part), musculus rectus femoral (15 cm above patella) and m. abductor hallucis (middle part). Electrical pain thresholds (EPT) will be tested by use of the QST-3 device (JNI Biomedical ApS, Klarup, Denmark) on the left and right body side. Meas- urement locations are the musculus trapezius pars me- dian (middle part) and the musculus rectus femoris (20 cm above patella). Electrical pain thresholds (EPT) are assessed and expressed in milli-Ampère. Single pulse evoked pain measurement is performed by one pulse at 150% of the EPT and assessed on a VAS. Sum- mation (i.e. Electric Wind-Up response (E-WUR)) is measured by a train of five pulses at 150% of the EPT and assessed on as VAS. Conditioned Pain Modulation (CPM) [23,25] will be assessed. Electrical Pain Toler- ance Thresholds (EPTT) (test stimulation) are assessed and expressed in milli-Ampère on the m. Rectus femoris contralateral to the dominant hand. The noxious stimu- lus (conditioning stimulation) is to immerse the dom- inant hand until the wrist in a bucket filled with water and icecubes (‘Ice water bucket test’) [24] for ‘as long as possible, until the moment that the sensa- tion becomes unbearable and you want to stop dir- ectly”. The pain will be recorded every 10 seconds on a NRS. The duration of the immersion (with a max- imum of three minutes) will be recorded and the pain at the end of the immersion will be asked. Afterwards, again the EPTT and the PPT on the contra lateral m. rectus femoris are assessed.
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Effects of intensity of electroacupuncture on chronic pain in patients with knee osteoarthritis: a randomized controlled trial

Effects of intensity of electroacupuncture on chronic pain in patients with knee osteoarthritis: a randomized controlled trial

The concept of conditioned pain modulation (CPM), previously referred to as diffuse noxious inhibitory con- trols (DNIC), indicates that under normal conditions, pain can be attenuated by conditioning to a remote body region [12]. The endogenous analgesic system is critical for handling noxious events, and the strength of CPM function can predict the potential of developing chronic pain [13 – 15]. Quante and colleagues reported that neur- onal plasticity of the descending pain inhibitory system impacts CPM function, which is diminished during the development of KOA [16]. Previous study has demon- strated that high intensity of EA (> 2 mA) is similar to a noxious stimulus and may activate CPM function effect- ively in rats [10]. Thus, we hypothesized that high inten- sity of EA (strong EA) may be more effective on chronic pain in patients with KOA by strengthening the CPM function. To validate this hypothesis, we undertook this randomized controlled trial to compare the effect of strong EA with weak EA or sham EA on chronic pain in patients with KOA.
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<p>Sleep, Experimental Pain and Clinical Pain in Patients with Chronic Musculoskeletal Pain and Healthy Controls</p>

<p>Sleep, Experimental Pain and Clinical Pain in Patients with Chronic Musculoskeletal Pain and Healthy Controls</p>

(8 a.m.) by laboratory sessions, which were procedurally equal and designed to assess three domains, namely cortisol, atten- tion, and pain. At the beginning and end of each laboratory session, participants provided a saliva sample for later deter- mination of cortisol levels. Further, two attention-related tests (dot-probe task and eye-tracking paradigm with emotional facial stimuli), which allowed to check for in fl uences of sleep on attentional measures, and a laboratory pain testing to examine effects of sleep on pain were implemented. Pain testing consisted of the assessment of pressure pain thresholds (PPTs), followed by the assessment of temporal summation of pain (TSP) and conditioned pain modulation (CPM). After the experimental pain test, participants completed the Situational Catastrophizing Questionnaire (SCQ; state version of pain catastrophizing) 21 to assess catastrophizing thoughts in rela- tion to the just experienced pain. At the end of the evening sessions, a portable PSG device was installed and a questionnaire to assess subjective sleep parameters (evening and morning protocols) was handed out. 22 At the beginning of the morning sessions, the PSG device was detached and a further laboratory session followed. Additional question- naires about sleep (Pittsburgh Sleep Quality Index (PSQI)) 23 and pain (Pain Catastrophizing Scale (PCS); trait version of pain catastrophizing) 24 as well as clinical pain (German Pain Questionnaire (DSF); assessment of pain intensity and pain duration in the sample of chronic pain patients) 25 were com- pleted at the end of the fi rst morning session.
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Effects of the carrier frequency of interferential current on pain modulation in patients with chronic nonspecific low back pain: a protocol of a randomised controlled trial

Effects of the carrier frequency of interferential current on pain modulation in patients with chronic nonspecific low back pain: a protocol of a randomised controlled trial

Methods/design: A three-arm randomised controlled trial with patient and assessor blinded to the group allocation. One hundred fifty patients with chronic, nonspecific low back pain from outpatient physical therapy clinics in Brazil. The patients will be randomly allocated into 3 groups (IFC 1 kHz, IFC 4 kHz or Placebo IFC). The interferential current will be applied three days per week (30 minutes per session) over four weeks. Primary outcome: Pain intensity. Secondary outcomes: The pressure pain threshold, global impression of recovery, disability, function, conditioned pain modulation and temporal summation of pain, discomfort caused by the current. All outcomes will be measured at 4 weeks and 4 months after randomisation. The between-group differences will be calculated by using linear mixed models and Tukey ’ s post-hoc tests.
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Descending pain modulation in irritable bowel syndrome (IBS): a systematic review and meta-analysis

Descending pain modulation in irritable bowel syndrome (IBS): a systematic review and meta-analysis

The outcome of interest is descending pain modulation function in people with IBS as assessed by neurophysio- logical testing i.e. conditioned pain modulation (CPM) or offset analgesia (OA). The neurophysiological proto- col has to use a painful test stimulus assessed both prior to and during and/or after the presentation of a condi- tioning stimulus. Descending pain modulation in the control group would be expected to be quantified as normally responsive. Those studies where descending pain modulation in control participants are not quanti- fied as normally responsive, will be examined as a poten- tial source of variability and will be considered as a candidate for a stratified meta-analysis.
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Melatonin in Pain Modulation: Analgesic or Proalgesic?

Melatonin in Pain Modulation: Analgesic or Proalgesic?

Nitric-oxide (NO) as a second message involved in neuroprotection, neurotoxicity, neurotransmission, and neu- roplasticity also played an important role [36]. Evidences suggested that melatonin was able to modulate NO. Esposoto et al. [37] showed that melatonin was able to blocked protein nitration affecting inducible nitric-oxide synthase (iNOS) expression in paw tissue thus to improve tissue damage and inflammation. Result of Alfonso et al. [25] suggested NO involved in pain modulation of melatonin in formalin test through NO-cyclic GMP-pro- tein kinase G-K+ channels pathway. Interestingly, as Kawabata et al. [38] reported NO showed a dual role (analgesic/proalgesic) in pain modulation in different dosages. Callsen-Cencic, P. et al. [36] thought that spinal neuronal nitric oxide synthase expression critically depend on the type of afferent fibers activated by a specific lesion as well as the intensity and duration of input to the spinal cord. A recent review concludes complex pain modulatory action of NO [39]. The dual effect of NO in pain modulation might explain the conflicting results of melatonin in different experiments to some extent.
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Evaluation of the Bonapace Method: a specific educational intervention to reduce pain during childbirth

Evaluation of the Bonapace Method: a specific educational intervention to reduce pain during childbirth

Subjects for this study were recruited among patients of five medical clinics, affiliated with general hospitals, where no midwifery continuity of care programs were available, in the province of Quebec between 1995 and 1998. Subjects were informed of the nature of the study, which sought to better understand the perception of pain during childbirth, during their routine visit to the doctor, by a nurse or a research agent guided by a written protocol. Nothing was mentioned in rela- tion to the correlation between the type of training and the perception of pain. All participating subjects were instructed on how to measure pain during labor and delivery using VAS. Each participant signed a consent form and received a pain management questionnaire to be completed during childbirth. After giving birth, they completed the demographic section of the questionnaire (age, parity, finances, education, onset of labor, and childbirth training). In accordance with the Univer- sité du Québec en Abitibi-Témiscamingue Human Subjects Ethics Committee, each subject was informed of her right to withdraw from the experiment at any time without prejudice. In consideration of the ethical problem involved in randomly imposing one type of treatment over another, the complexity involved in recruiting subjects for this study, and the need to determine the potential for a large, randomized controlled trial, we allowed subjects to assign themselves, during pregnancy, to the training program that best reflected their preferences: TCTP or the BM. All training programs were available at local community facilities, free of charge.
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Noxious counterirritation in patients with advanced osteoarthritis of the knee reduces MCC but not SII pain generators: A combined use of MEG and EEG

Noxious counterirritation in patients with advanced osteoarthritis of the knee reduces MCC but not SII pain generators: A combined use of MEG and EEG

that later components in the pain-evoked potentials that are generated by limbic brain structures such as the cingulate cortex processing cognitive and emotion aspects of pain yield greater attenuation by tonic pain than middle-latency components indicating sensory-discriminative aspects of pain processed in the somatosensory cortex (Lorenz and Garcia-Larrea 2003). It is, therefore, possible that painful counterirritation in experimental studies with normal subjects exerted a stronger cognitive-emotional reaction and distrac- tion from phasic electrical stimuli than did the provoked knee pain in our patients. However, inhibition of phasic pain by noxious counterirritation as explained in the theory of DNIC involves a distinct spino-bulbo-spinal feedback- loop that goes beyond a pure distraction effect (Le Bars et al 1979a, 1979b; Willer et al 1984; Lautenbacher et al 2007). Furthermore, nociceptive input is modulated by multiple endogenous mechanisms coordinated by the periaqueductal grey (PAG) and rostroventral medulla (RVM) network which receives extensive input from the limbic forebrain such as the prefrontal cortex, insular cortex and rostral cingulate gyrus (Basbaum and Fields 1978; Dubner and Ren 1999). It is currently unclear whether these pathways involving supra- spinal sites contribute to DNIC or whether it comprises a more specifi c pathway as originally suggested. Therefore, we use the term DNIC here more generally as neurophysiologic correlate of the pain inhibiting pain phenomenon.
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