Abstract: CXCR3 is a well-known receptor involved in immune cell recruitment and inflammation. Pathological inflammation leads to pain stimulation and hence nociception. Therefore, we decided to review the recent research on CXCR3 to identify its precise role in the modulation of pain in a variety of clinical conditions targeting various regions of the body. Studies were selected from PubMed Medline, which relate CXCR3 to the progression of diseases with either bone cancer pain, neuropathic pain, cystitis pain, osteoarthritis and rheumatoid arthritis pain, dental pain, in particular, periodontitis and pulpitis. In all the diseases studied, a high prevalence of CXCR3 and/or its ligand were identified where CXCR3 is a key player in the pathophysiological process of many inflammatory conditions. CXCR3 and its ligands, particularly CXCL10, modulate nociception via actions in the dorsal root ganglia and dorsal horn of the spinal cord, in cases of bone cancer pain, neuropathic, and joint pain. However, with the other studied disease, no direct link to pain has been made, although it contributes to the pathological progression of the diseases and hence would be a causal factor for the pain. Furthermore, CXCR3 appears to play a role in desensitizing the opioid receptor in the descending modulatory pathway within the brain stem as well as modulating opioid-induced hyperalgesia in the dorsal horn of the spinal cord. Further research is required for understanding the exact mechanisms of CXCR3 in painmodulation centrally and peripherally. A greater understanding of the immunological activities and pharmacological consequence of CXCR3 and its ligands could help in the discovery of newer drugs for modulating pain arising from pathogenic or inflammatory sources. Given the significance of the CXCR3 for nociception, its utilization may prove to be beneficial as a target for analgesia.
The following data will be collected from the included studies. General study information: authors, year of pub- lication, sample size, language; study design: cross- sectional, case-control, observational study or clinical trial; clinical setting: primary care, specialist clinic, hos- pital outpatient department; participant characteristics: age, gender, classification or diagnostic criteria used, duration of pain, severity of pain; measure of descending painmodulation: conditioning stimulus, test stimulus, outcome measure and time points outcome measure were recorded; measure of cognitive processes and mood: assessment type used.
dynic has not got an accordant answer -. Mocina et al.  reported that intrathecal (3 - 100 microg) and oral (37.5 - 300 mg/kg) administration of melatonin decreased tactile allodynia in rats induced by spinal nerve ligation, while intrathecal/oral administration of MT2 and opioid receptors antagonist dismissed antiallo- dynic effect of melatonin in a dose-dependent manner. However, Ahmet et al.  reported that intraperitoneal (30, 60, 120 mg/kg) and intracerebroventricular (0.001, 0.01, 0.1 nmol) melatonin exerted its antihyperalgesic effect but not antiallodynia in mice through larginine-Nitric oxide pathway and opioid system. Assumed that hyperalgesic and allodynic were mediated by different nerve fibers and melatonin was more sensitive to small diameter unmyelinated high threshold C-fiber. Interestingly, Zurowski D. et al.  reported opposite result that intraperitoneal administration (100 mg/kg) of exogenous melatonin abolished mechanical allodynia but not thermal hyperalgesia in rat chronic constriction injury. And this effect could be almost blunted by nonselective opioid receptor antagonist naloxone and MT1/MT2 antagonist luzindole. They thought the influence of melato- nin on the process of thermal hyperalgesia is based rather on its anti-inflammatory effect than on the opioid sys- tem activation. Rayleigh Ping et al.  reported that in rats melatonin dose-dependently improved behavioral hypersensitivity by attenuating p-p38 MAPK levels and release of proinflammatory cytokines; meanwhile, pi- nealectomy which caused a reduction in endogenous melatonin levels exacerbated these effects. All these con- flicting results did implicate that various and complex mechanisms of melatonin involved in painmodulation.
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 painmodulation 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.
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 PainModulation (CPM) was given. Thus according to those studies, multireceptive neurons are also activated by non-noxious stimuli.
Methods: A systematic review and meta-analysis will be conducted. Terms related to diabetes, pain thresholds and painmodulation mechanisms will be combined in a structured search in MEDLINE, CINAHL, EMBASE, the Cochrane Library, SPORTDiscus, Web of Science and PEDro. Publications on adults (18 years and older) with diabetes and at least one pain threshold measure following thermal, mechanical or electrical stimuli and/or at least one painmodulation mechanisms (temporal summation or conditioned painmodulation) with a comparison group will be considered. There will be no restriction regarding language or year of publication. One investigator will screen records based on title and abstract (ESS). Two independent investigators (ESS and MC) will select full-text papers and assess risk of bias using a modified Downs and Black checklist. Potential disagreements will be resolved with a third investigator (LB). One investigator (ESS) will extract all data and a second investigator (MS) will extract data for 20% of the papers to verify accuracy of the process. A sensitivity analysis for publication bias will be conducted.
diabetic neuropathy, impaired CPM was shown to cor- relate with an improved clinical response to duloxetine, a serotonin–norepinephrine reuptake inhibitor (SNRI). This finding was interpreted as indicating that treatment with an SNRI could restore more efficient CPM, thus being particu- larly useful for patients with a baseline CPM impairment. Further elaborating on this notion, it has subsequently been proposed that experimental methods can be used to establish a painmodulation profile, based on the measurement of CPM as well as temporal summation, thus establishing a pain inhibitory/facilitatory balance; the assumption being that this pain phenotype may be used to position individuals on a pronociceptive/antinociceptive spectrum. 39 While the
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 . 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 painmodulation with CHEP as a test stimulus and painful heat as conditioning stimulus  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.
OXT is very similar to arginine vasopressin (AVP) in the structure, synthesis, source and distribution . In- tra-NRM microinjection of AVP increases the pain threshold, and local administration of vasopressin recep- tor antagonist decreases the pain threshold . Through method of generated an OXT receptor-receptor mouse, in which part of the OXT receptor gene is replaced with Venus cDNA (a variant of yellow fluorescent protein), is to more precisely characterize OXT receptor-expressing neurons, Yoshida et al. has found that there are many OXT recaptors in the raphe nuclei including NRM . Pain stimulation can change OXT concentration in the NRM tissue [5,6]. However, it is still not clear how OXT in the NRM influences painmodulation. The present study was tried to investigate OXT in the rat NRM effect on painmodulation.
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 painmodulation; 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.
Objective: Chronic pain is believed to be related to a dysfunction of descending pain modulatory mechanisms. Functioning of descending painmodulation can be assessed by various methods, including conditioned painmodulation (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.
of maternal pain anxiety on girls’ anxiety related to such a “pain inhibits pain” task, and to the magnitude of an observed CPM effect for boys. The mechanisms underlying these associations should be explored in future research. It is possible that parental influences, such as anxiety about pain, have a profound developmental effect upon the emer- gence of central pain inhibitory systems, especially in boys. Longitudinal work addressing a range of parental psychologi- cal factors and the development of children’s endogenous pain inhibitory capacity over time should be undertaken to parse out the cause and effect relationship between parental psychological health and children’s central painmodulation. In addition, future research should investigate the extent to which children’s central inhibitory pain processes may be influenced by interventions targeting pain-related anxiety in parents via behavioral modification.
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)  and that of levodopa is generally estimated as 0.7 to 1.4 h , the latter can last up to 7.9 days . The residual dopaminergic concentration might therefore still have induced antinociceptive effects  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 . 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.
Regarding the influence of sex on CPM stability within and between sessions, the present study revealed that the stability of CPM within and between days differed by sex (Tables 2 and 4). A number of studies using widely different methodologies have investigated sex differences in experimental pain sensitivity  using CPM, or other paradigms. Some researchers suggest less efficient CPM in women than men [14,26,46] while other studies did not detect sex differences in CPM [47,48]. Several fac- tors have been proposed to explain sex differences; how- ever the stability of this experimental pain measure across sexes had not been explored before. In this study, ICC’s stratified by sex showed that males from the clinical cohort showed lower scores than females (within session), and the females from the healthy cohort showed lower scores than males (within and between session for the absolute difference). Furthermore, the standard error of measurement (SEM) is directly related to the reliability of a test; that is, the larger the SEM, the lower the reliabil- ity of the test and the less precision in the measures taken and scores obtained. Consequently, our results showed a large difference on SEM between males and females, where males from the healthy cohort and females from the clinical cohort had lower levels of standard error of measurement indicating higher levels of score consistency. The results of the present study in two musculoskel- etal pain models suggest that the most stable situation to use a CPM paradigm is in females from the clinical cohort (where changes need to exceed a MDC of 16 to exceed measurement error) and males from the healthy
There are a few limitations of this study. All the experimental pain tasks were acute, painful laboratory experiences which the participants had control over. The cold pressor pain intensity was recorded every 15 s and the average was used for analysis. This was one of the limitations of the study in that the number of times cold pressor pain intensity was recorded could vary between participants, depending on the tolerance of the partici- pants. Results from these tasks may be less generalizable to the clinical populations. However, several studies have used these experimental pain procedures to predict clin- ical pain. 51,52 Socioeconomic status such as income and educational level is reported to be associated with inci- dence of pain. 53 Due to the lack of information on our participants ’ socioeconomic status, the impact of socio- economic status on racial difference cannot be deter- mined. The cross-sectional design of our study also did not allow a determination of the causal relationship between the observed racial differences and outcome such as pain severity. Nonetheless, the strengths of the present study had been demonstrated, ie the participants were age- and sex-matched, with care taken to collect data during a standardized phase of menstrual cycle of female participants.
Two experiments by de Wied et al. (2001) showed the content of the emotional cue can also have an influence on pain processing. Participants seeing pictures of people in pain had low pain thresholds; in contrast, negative pictures without a painful element seemed to have the same effect on pain thresholds as neutral pictures. According to Preston and de Waal (2002), perception of emotion activates the neural mechanisms that are responsible for the generation of emotions, described as the perception action model. This can also be the case for observing pain or ‘empathy for pain’ (Fan & Han, 2008; Singer, Seymour, O’Doherty, Kaube, Dolan & Frith, 2004; Ushida et al., 2008). The recent growing neuroscientific research on empathy for pain contributes to the knowledge about the effects of observed pain on brain areas involved in actual pain. From research on empathy for pain, it is clear that seeing someone else in pain activates the brain regions involved in the emotional-motivational aspects of pain: the ACC, insula and thalamus (Botvinick, Jha, Bylsma, Fabian, Solomon & Prkachin, 2005; Fan et al., 2008; Jackson, Brunet, Meltzoff & Decety, 2006; Jackson, Meltzoff and Decety, 2005; Morrison & Downing, 2007; Morrison, Lloyd, di Pellegrino & Roberts, 2004; Singer et al., 2004). But, researchers also found activation in the SI during processing of pain of others (Bufalari, Aprile, Avenanti, Di Russo & Aglioti, 2007). Not many researchers have examined the effects of empathy for pain on pain processing yet. Godinho, Magnin, Perchet and Garcia-Larrea (2006) found that pictures showing physical pain content enhanced SEP amplitudes in comparison to unpleasant pictures without reference towards pain. The effect was found later than 270 ms. Valeriani et al (2008) showed that observation of needle penetration reduced the N1/P1 component of the SEP, indicating effects of empathy for pain on SI and SII. The effects were explained by the competitive influence of the observed pain stimuli and painful stimulation. So, both Godinho et al. (2006) and Valeriani et al. (2008) found effects of empathy for pain on SEPs, but the temporal characteristics remain a topic for discussion.
Results: Fifty-two individuals were enrolled: 19 episodic migraine patients, 18 chronic migraine patients, and 15 controls. The analysis of the fractional anisotropy in the ROIs showed that those patients with the poorest prognosis (i.e., those with chronic migraine despite therapy at six months -long-term chronic migraneurs) had a significantly lower fractional anisotropy in the right ROIs. Participants with higher cognitive reserve also had greater fractional anisotropy in the right anterior insula and both cingulate gyri. Multivariate analysis showed a significant association between cognitive reserve, migraine frequency, and fractional anisotropy in the right-sided regions of interest. Conclusions: Long-term chronic migraine patients show abnormalities in anterior white matter tracts, particularly of the right hemisphere, involved in painmodulation emotion, cognition and resilience. Robustness in these areas is associated with a higher cognitive reserve, which in turn might result in a lower tendency to migraine chronification.
(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 painmodulation (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.
Different mechanisms, as sensitization of peripheral nociceptores, can be linked to long-term changes at spinal and supra spinal levels. This phenomenon induces an increase in the sensitivity of dorsal horn nociceptive circuits and/or neuroimmune activation (Schwaller and Fitzgerald, 2014). It is important to note that the descending inhibitory mechanisms are not completely formed until the third week of life (Nandi and Fitzgerald, 2005). Studies have shown that extensive remodeling of opioid receptor expression occurs in the first three postnatal weeks (Beland and Fitzgerald, 2001; Rahman and Dickenson, 1999; Rahman et al., 1998). Furthermore, previous study showed that a repeated needle prickling on the right paw at neonatal rats promoted long-lasting changes linked to mechanical hyperalgesia. This increases glial markers density in cortical areas involved in the pain process and pain interpretation (Sanada et al., 2014). Our previous study showed increased analgesic response after repeated morphine administration (between eighth (P8) and fourteenth (P14) old days) without developing opioid tolerance (Rozisky et al., 2008). Furthermore, in another study, we observed a decrease in the nociceptive response in the first phase of formalin test after unique fentanyl administration in rats at P14 (Medeiros et al., 2012). It is interesting to note that the opioid analgesics, such as morphine, are the most effective and frequently used substances for the relief of moderate to severe pain in adults, and children (El Sayed et al., 2007; Suresh and Anand, 2001; Lima et al., 1996). In this way, it is important to investigate the involvement opioidergic and GABA systems in the surgery painmodulation in the infant age. Considering the exposed above and the theme relevance, we suggest that surgical procedures, pain and pharmacological manipulations at neonatal and infant age can lead to behavioral and biochemical alterations until the adult age. There are a few studies about the experience of pain in neonates and children and there is a limited research in the basic area. Therefore, the aim of the present study was to investigate the impact of surgical procedures in early life and the involvement of opioidergic and GABAergic pathways on the rat surgery pain through two different experimental designs: A) experimental design 1 evaluated the short (P21) and long-lasting (P45) effect of early surgical procedure on rats’ nociceptive
Significant inter-subject heterogeneity in acupuncture treatment response has been noted and may be at least partially related to patients’ coping strategy toward acu- puncture and/or their clinical pain. For instance, a recent study  showed that acupuncture treatment in patients with chronic musculoskeletal pain enhanced their coping towards pain (e.g. positive reframing) as well as reducing pain intensity. Another study  emphasized the positive influence of acupuncture’s long-term effect on cognitive and emotional pain coping in chronic low back pain pa- tients. It is also possible that coping strategy can modulate clinical outcomes. For instance, Koh et al.  suggested using a treatment approach based on the individual’s cop- ing strategy for the effective treatment of cancer patients. For chronic pain, rheumatoid arthritis patients using a passive coping strategy also reported higher levels of clin- ical pain intensity . In evoked, experimental pain stud- ies, Hayes et al. used a cold pressor task and demonstrated greater pain tolerance for an acceptance coping approach , while Keogh et al.  showed gender differences in cold pain ratings under different coping instructions (emo- tion- and sensory-focused coping). These results emphasize the impact of coping strategy on painmodulation. We