Endogenous Pain Inhibitory Systems Research Articles

Nucleus accumbens dopamine receptors mediate the stress-induced analgesia in an animal model of acute pain

Exposure to aversive stimuli such as stress results in profound analgesia named stress-induced analgesia (SIA). We previously showed that D1- and D2-like dopamine receptors within the nucleus accumbens (NAc) mediated the SIA in chronic pain. Since the neurophysiological mechanisms responsible for the various pain conditions are different, the present study aimed to examine the role of dopamine receptors within the NAc in the forced swim stress (FSS)-induced analgesia in the tail-flick test as an animal model of acute pain. Ninety-six adult male Wistar rats weighing 200–230 g were unilaterally implanted with a cannula into the NAc. SCH23390 or Sulpiride (0.25, 1, and 4 μg/0.5 μl vehicle), as D1- and D2-like dopamine receptor antagonists, respectively, were microinjected into the NAc, 5 min before exposure to FSS. The vehicle groups received saline or DMSO instead of SCH23390 or Sulpiride, respectively. The tail-flick test was performed in time set intervals after animals were subjected to FSS. The results showed that FSS produces analgesia during the tail-flick test. However, intra-accumbal injection of SCH23390 or Sulpiride attenuated the FSS-induced analgesia. D1-and D2-like dopamine receptor antagonists contributed almost equally to attenuating the antinociceptive responses induced by FSS. It seems that the mesolimbic dopamine system might act as a potential endogenous pain control system in stress conditions. Besides, an improved understanding of this endogenous pain inhibitory system can develop pharmacological and psychological approaches to treat pain.

Risk factors of pain, physical function, and health-related quality of life in elderly people with knee osteoarthritis: A cross-sectional study

Data on the precise mechanisms of the complex interactions of factors related to clinical impact of knee osteoarthritis (KOA) in the elderly population remain limited. To find predictors that explain pain intensity, physical function, and quality of life in elderly KOA subjects, we performed a cross-sectional analysis of the baseline data from a randomized trial. The trial included 104 subjects (aged ≥60) with KOA pain and dysfunctional endogenous pain-inhibitory system activity assessed by conditioned pain modulation (CPM). Three multiple linear regression models were performed to understand the independent predictors of Brief Pain Inventory (BPI), WOMAC function subscale (WOMACFunc), and SF-12 physical subscale (SF12-PCS). Model 1 showed that BPI pain score was predicted by low CPM response, high von-Frey light touch threshold, worse radiological severity as indexed by Kellgren-Lawrence grade (KL), high von-Frey punctate pain intensity and high levels of anxiety (adjusted R2 = 27.1%, F (6,95) = 7.27, P < 0.0001). In model 2, von-Frey light touch threshold, KL, depressive symptoms indexed by Beck Depression Inventory (BDI), level of sleepiness and pain pressure threshold were risk factors for SF12-PCS (adjusted R2 = 31.9%, F (5,96) = 10.5, P < 0.0001). Finally, model 3 showed that WOMACFunc was predicted by BDI, KL and BPI (adjusted R2 = 41%, F (3,98) = 24.42, P < 0.0001). Our data provides an interesting framework to understand the predictors of KOA pain in the elderly and highlights how its related outcomes are affected by disease-specific factors, somatosensory dysfunction and emotional factors.

Muscle stretching – the potential role of endogenous pain inhibitory modulation on stretch tolerance

Background and aims The effect of stretching on joint range of motion is well documented and is primarily related to changes in the tolerance to stretch, but the mechanisms underlying this change are still largely unknown. The aim of this study was to investigate the influence of a remote, painful stimulus on stretch tolerance. Methods Thirty-four healthy male subjects were recruited and randomly assigned to an experimental pain group (n=17) or a control group (n=17). Passive knee extension range of motion, the activity of hamstring muscles and passive resistive torque were measured with subjects in a seated position. Three consecutive measures were performed with a 5-min interval between. A static stretch protocol was utilized in both groups to examine the effect of stretching and differences in stretch tolerance between groups. Following this, the pain-group performed a cold pressor test which is known to engage the endogenous pain inhibitory system after which measurements were repeated. Results A significant increase in knee extension range of motion was found in the pain group compared with controls (ANCOVA: p<0.05). No difference was found in muscle activity or passive resistive torque between groups (ANCOVA p>0.091). Conclusions Passive knee extension range of motion following stretching increased when following a distant, painful stimulus, potentially engaging the endogenous pain inhibitory systems. Current findings indicate a link between increased tolerance to stretch and endogenous pain inhibition. Implications The current findings may have implications for clinical practice as they indicate that a distant painful stimulus can influence range of motion in healthy individuals. This implies that the modulation of pain has significance for the efficacy of stretching which is important knowledge when prescribing stretching as part of rehabilitation.

Developing an optimized strategy with transcranial direct current stimulation to enhance the endogenous pain control system in fibromyalgia

ABSTRACTIntroduction: Fibromyalgia affects more than 5 million people in the United States and has a detrimental impact on individuals’ quality of life. Current pharmacological treatments provide limited benefits to relieve the pain of fibromyalgia, along with a risk of adverse effects; a scenario that explains the increasing interest for multimodal approaches. A tailored strategy to focus on this dysfunctional endogenous pain inhibitory system is transcranial direct current stimulation (tDCS) of the primary motor cortex. By combining tDCS with aerobic exercise, the effects can be optimized.Areas covered: The relevant literature was reviewed and discussed the methodological issues for designing a mechanistic clinical trial to test this combined intervention. Also, we reviewed the neural control of different pathways that integrate the endogenous pain inhibitory system, as well as the effects of tDCS and aerobic exercise both alone and combined. In addition, potential neurophysiological assessments are addressed: conditioned pain modulation, temporal slow pain summation, transcranial magnetic stimulation, and electroencephalography in the context of fibromyalgia.Expert commentary: By understanding the neural mechanisms underlying pain processing and potential optimized interventions in fibromyalgia with higher accuracy, the field has an evident potential of advancement in the direction of new neuromarkers and tailored therapies.

Effects of Transcranial Direct Current Stimulation on Knee Osteoarthritis Pain in Elderly Subjects With Defective Endogenous Pain-Inhibitory Systems: Protocol for a Randomized Controlled Trial.

BackgroundKnee osteoarthritis (OA) has been the main cause behind chronic pain and disabilities in the elderly population. The traditional treatment for knee OA pain currently concerns a number of combinations of pharmacological and nonpharmacological therapies. However, such combinations have displayed little effects on a significant group of subjects. In addition to this, pharmacological treatments often cause adverse effects, which limits their use on this population. Previous studies showed that chronic knee OA pain may be associated with maladaptive compensatory plasticity in pain-related neural central circuits indexed by a defective descending pain-inhibitory system. Transcranial direct current stimulation (tDCS) can revert some of these maladaptive changes, thus decreasing chronic pain sensation. Numerous studies have demonstrated that the use of anodal tDCS stimulation over the primary motor cortex (M1) has positive effects on chronic neuropathic pain. Yet, data on OA pain in elderly patients, including its effects on the endogenous pain-inhibitory system, remain limited.ObjectiveThe objective of this study is to evaluate the efficacy of tDCS in reducing pain intensity caused by knee OA in elderly subjects with defective endogenous pain-inhibitory systems.MethodsWe designed a randomized, sham-controlled, single-center, double-blinded clinical trial. Patients with knee OA who have maintained a chronic pain level during the previous 6 months and report a pain score of 4 or more on a 0-10 numeric rating scale (NRS) for pain in that period will undergo a conditioned pain modulation (CPM) task. Participants who present a reduced CPM response, defined as a decrease in NRS during the CPM task of less than 10%, and meet all of the inclusion criteria will be randomly assigned to receive 15 sessions of 2 mA active or sham tDCS for 20 minutes. A sample size of 94 subjects was calculated. The Brief Pain Inventory pain items will be used to assess pain intensity as our primary outcome. Secondary outcomes will include pain impact on functioning, mobility performance, quality of life, CPM, pressure pain threshold, touch-test sensory evaluation, and safety. Follow-up visits will be performed 2, 4, and 8 weeks following intervention. The data will be analyzed using the principle of intention-to-treat.ResultsThis study was approved by the institutional review board with the protocol number 1685/2016. The enrollment started in April 2018; at the time of publication of this protocol, 25 subjects have been enrolled. We estimate we will complete the enrollment process within 2 years.ConclusionsThis clinical trial will provide relevant data to evaluate if anodal tDCS stimulation over M1 can decrease chronic knee OA pain in elderly subjects with defective CPM. In addition, this trial will advance the investigation of the role of central sensitization in knee OA and evaluate how tDCS stimulation may affect it.Trial RegistrationClinicalTrials.gov NCT03117231; https://clinicaltrials.gov/ct2/show/NCT03117231 (Archived by WebCite at http://webcitation.org/73WM1LCdJ)International Registered Report Identifier (IRRID)RR1-10.2196/11660

Endogenous Pain Modulation Profiles Among Individuals With Chronic Pain: Relation to Opioid Use

It is generally assumed that individuals exhibiting high pain inhibition also tend to exhibit low pain facilitation, but little research has examined this association in individuals with pain. The aims of this cross-sectional study were 1) to examine the association between measures of conditioned pain modulation (CPM) and temporal summation (TS) in individuals with chronic pain, and 2) to examine whether this association was moderated by demographic (age, sex), psychological (depression, catastrophizing), or medication-related (opioid use) variables. Individuals (N= 190) with back or neck pain completed questionnaires and underwent a series of quantitative sensory testing procedures assessing CPM and TS. Results indicated that individuals with higher levels of CPM showed lower levels of TS, r = –.20, P < .01. Analyses, however, revealed that the magnitude of this association was substantially weaker among opioid users (r= –.08, NS) than nonusers (r= −.34, P < .01). None of the demographic or psychological variables included in our study influenced the association between CPM and TS. The magnitude of CPM was lower for opioid users than nonusers, suggesting that opioid use might dampen the functioning of endogenous pain-inhibitory systems and possibly contribute to a discordance between measures of pain inhibition and pain facilitation. PerspectiveResults of the present study indicated that greater endogenous pain-inhibitory capacity is associated with lower levels of pain facilitation. This association, however, was not significant among opioid users, suggesting that opioids might compromise the functioning and interrelationship between endogenous pain modulatory systems.

Reduced endogenous pain inhibition in adolescent girls with chronic pain.

Background and aims Chronic pain is affecting a growing number of individuals including adolescents. Different endogenous pain inhibitory systems could confer protection against development of chronic pain. Decreased pain perception can be observed following intense pain (i.e. conditioned pain modulation - CPM) or after physical exercise (i.e. exercise-induced analgesia - EIA). Reduced effectiveness of pain inhibitory mechanisms have been reported in several chronic pain conditions. However, the extent of these dysfunctions has not been thoroughly investigated in adolescents suffering from chronic pain. Our hypothesis was that adolescents suffering from chronic pain have less effective CPM and EIA than pain-free teenagers. Methods Twenty-five healthy adolescent girls and 16 teenage girls with chronic pain participated in this study. Only girls were included in this investigation, since chronic pain is more prevalent in females. The effectiveness of CPM was assessed by comparing heat pain stimulations (individually adapted to induce mild pain intensity) performed with a thermode before and after a cold pressor test (CPT; 2 min, 10 °C). EIA was evaluated by comparing pain intensity produced by an ice cube placed on the forearm before and after a graded exercise test on a cycle ergometer. Results Pain intensity produced by heat pain stimulations decreased following CPT in healthy (p<0.05), but not in chronic pain adolescent girls (p=0.4). Pain intensity induced by the ice cube was reduced after exercise in healthy (p<0.05), but not in chronic pain adolescents (p=0.9). The effectiveness of CPM and EIA was inferior in teenage girls suffering from chronic pain compared to healthy participants (p<0.05). Conclusions Endogenous pain inhibitory mechanisms triggered by intense pain or by physical exercise are effective in healthy adolescent girls. Teenage girls living with chronic pain do not show diminished pain perception after a CPT or a graded exercise test. These results suggest that pain inhibitory mechanisms such as CPM and EIA are ineffective in adolescent girls suffering from chronic pain. Implications In a wider context, the findings of the present research could help understand better the mechanisms involved in the development of chronic pain. Improved comprehension of this subject might help prevent chronic pain conditions and thus, reduce the negative impacts of this burden.

Diffuse noxious inhibitory controls and brain networks are modulated in a testosterone-dependent manner in Sprague Dawley rats

Diffuse noxious inhibitory control (DNIC), which involves endogenous pain modulation, has been investigated as a potential mechanism for the differences in pain modulation observed between men and women, though the literature shows contradictory findings. We used a capsaicin-induced DNIC behavioral assay and resting state functional magnetic resonance imaging (rsfMRI) to assess the effect of testosterone on pain modulation and related brain circuitry in rats. We hypothesized that testosterone is required for DNIC that leads to efficient pain inhibition by increasing descending pain modulation. Male, female, and orchidectomized (GDX) male rats had a capsaicin injection into the forepaw to induce DNIC and mechanical thresholds were observed on the hindpaw. rsfMRI scans were acquired before and after capsaicin injection to analyze the effects of DNIC on periaqueductal gray (PAG), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) connectivity to the whole brain. The strength of DNIC was higher in males compared to females and GDX males. PAG connectivity with prelimbic cortex (PrL), ACC and insula was stronger in males compared to females and GDX males, whereas females and GDX males had increased connectivity between the right ACC, hippocampus and thalamus. GDX males also showed a stronger connectivity between right ACC and NAc, and right NAc with PrL, ACC, insula and thalamus. Our findings suggest that testosterone plays a key role in reinforcing the endogenous pain inhibitory system, while circuitries related to reward and emotion are more strongly recruited in the absence of testosterone.

Prediction of persistent post-surgery pain by preoperative cold pain sensitivity: biomarker development with machine-learning-derived analysis

BackgroundTo prevent persistent post-surgery pain, early identification of patients at high risk is a clinical need. Supervised machine-learning techniques were used to test how accurately the patients’ performance in a preoperatively performed tonic cold pain test could predict persistent post-surgery pain. MethodsWe analysed 763 patients from a cohort of 900 women who were treated for breast cancer, of whom 61 patients had developed signs of persistent pain during three yr of follow-up. Preoperatively, all patients underwent a cold pain test (immersion of the hand into a water bath at 2–4 °C). The patients rated the pain intensity using a numerical ratings scale (NRS) from 0 to 10. Supervised machine-learning techniques were used to construct a classifier that could predict patients at risk of persistent pain. ResultsWhether or not a patient rated the pain intensity at NRS=10 within less than 45 s during the cold water immersion test provided a negative predictive value of 94.4% to assign a patient to the “persistent pain” group. If NRS=10 was never reached during the cold test, the predictive value for not developing persistent pain was almost 97%. However, a low negative predictive value of 10% implied a high false positive rate. ConclusionsResults provide a robust exclusion of persistent pain in women with an accuracy of 94.4%. Moreover, results provide further support for the hypothesis that the endogenous pain inhibitory system may play an important role in the process of pain becoming persistent.

Deep Brain Stimulation Improves the Symptoms and Sensory Signs of Persistent Central Neuropathic Pain from Spinal Cord Injury: A Case Report.

Central neuropathic pain (CNP) is a significant problem after spinal cord injury (SCI). Pharmacological and non-pharmacological approaches may reduce the severity, but relief is rarely substantial. While deep brain stimulation (DBS) has been used to treat various chronic pain types, the technique has rarely been used to attenuate CNP after SCI. Here we present the case of a 54-year-old female with incomplete paraplegia who had severe CNP in the lower limbs and buttock areas since her injury 30 years prior. She was treated with bilateral DBS of the midbrain periaqueductal gray (PAG). The effects of this stimulation on CNP characteristics, severity and pain-related sensory function were evaluated using the International SCI Pain Basic Data Set (ISCIPBDS), Neuropathic Pain Symptom Inventory (NPSI), Multidimensional Pain Inventory and Quantitative Sensory Testing before and periodically after initiation of DBS. After starting DBS treatment, weekly CNP severity ratings rapidly decreased from severe to minimal, paralleled by a substantial reduction in size of the painful area, reduced pain impact and reversal of pain-related neurological abnormalities, i.e., dynamic-mechanical and cold allodynia. She discontinued pain medication on study week 24. The improvement has been consistent. The present study expands on previous findings by providing in-depth assessments of symptoms and signs associated with CNP. The results of this study suggest that activation of endogenous pain inhibitory systems linked to the PAG can eliminate CNP in some people with SCI. More research is needed to better-select appropriate candidates for this type of therapy. We discuss the implications of these findings for understanding the brainstem’s control of chronic pain and for future progress in using analgesic DBS in the central gray.

Dorsal raphe nucleus acetylcholine-mediated neurotransmission modulates post-ictal antinociception: The role of muscarinic and nicotinic cholinergic receptors

The dorsal raphe nucleus (DRN) is a key structure of the endogenous pain inhibitory system. Although the DRN is rich in serotoninergic neurons, cholinergic neurons are also found in that nucleus. Both ictal and inter-ictal states are followed by post-ictal analgesia. The present study investigated the role of cholinergic mechanisms in postictal antinociceptive processes using microinjections of atropine and mecamylamine, muscarinic and nicotinic cholinergic receptor antagonists, respectively, in the DRN of rats. Intraperitoneal injection of pentylenetetrazole (PTZ) (at 64mg/kg) caused tonic and tonic-clonic seizures. The convulsive motor reactions were followed by an increase in pain thresholds, a phenomenon known as post-ictal analgesia. Pre-treatment of the DRN with atropine or mecamylamine at 1µg, 3µg and 5µg/0.2µL decreased the post-ictal antinociceptive phenomenon. The present results showed that the post-ictal analgesia was mediated by muscarinic and nicotinic cholinergic receptors in the DRN, a structure crucially involved in the neural network that organises post-ictal hypoalgesia.

Doubling Your Payoff: Winning Pain Relief Engages Endogenous Pain Inhibition

When in pain, pain relief is much sought after, particularly for individuals with chronic pain. In analogy to augmentation of the hedonic experience (“liking”) of a reward by the motivation to obtain a reward (“wanting”), the seeking of pain relief in a motivated state might increase the experience of pain relief when obtained. We tested this hypothesis in a psychophysical experiment in healthy human subjects, by assessing potential pain-inhibitory effects of pain relief “won” in a wheel of fortune game compared with pain relief without winning, exploiting the fact that the mere chance of winning induces a motivated state. The results show pain-inhibitory effects of pain relief obtained by winning in behaviorally assessed pain perception and ratings of pain intensity. Further, the higher participants scored on the personality trait novelty seeking, the more pain inhibition was induced. These results provide evidence that pain relief, when obtained in a motivated state, engages endogenous pain-inhibitory systems beyond the pain reduction that underlies the relief in the first place. Consequently, such pain relief might be used to improve behavioral pain therapy, inducing a positive, perhaps self-amplifying feedback loop of reduced pain and improved functionality.

Intrinsic connections within the pedunculopontine tegmental nucleus are critical to the elaboration of post‐ictal antinociception

This study investigated the intrinsic connections of a key-structure of the endogenous pain inhibitory system, the pedunculopontine tegmental nucleus (PPTN), in post-ictal antinociceptive process through synaptic inactivation of the PPTN with cobalt chloride. Male Wistar rats (n = 6 or 7 per group), weighing 250-280 g, had the tail-flick baseline recorded and were submitted to a stereotaxic surgery for the introduction of a guide-cannula aiming at the PPTN. After 5 days of postoperative recovery, cobalt chloride (1 mM/0.2 µL) or physiological saline (0.2 µL) were microinjected into the PPTN and after 5 min, the tail-withdrawal latency was measured again at 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, and 120 min after seizures evoked by intraperitoneal injection of pentylenetetrazole (64 mg/kg). The synaptic inactivation of PPTN decreased the post-ictal antinociceptive phenomenon, suggesting the involvement of PPTN intrinsic connections in the modulation of pain, during tonic-clonic seizures. These results showed that the PPTN may be crucially involved in the neural network that organizes the post-ictal analgesia.

Endogenous pain inhibition during menstrual cycle in migraine

Migraine is a common headache disorder that can vary menstrually in women and has been linked to an impairment of endogenous pain inhibitory systems. One of these endogenous pain inhibitory systems, namely conditioned pain modulation (CPM; formerly diffuse noxious inhibitory controls-like), has been shown to be affected by the menstrual cycle. The aim of this study was to examine CPM over the menstrual cycle in migraineurs and healthy controls. Twenty healthy women and 32 female migraineurs were examined on days 1, 4, 14 and 22 of the menstrual cycle. Detection and pain thresholds for electrocutaneous stimuli were first assessed at baseline. Second, tonic heat stimuli were applied concurrently to the electrical stimuli, and the difference in electrical thresholds to baseline were analysed as indicating CPM inhibition. Migraineurs revealed higher detection thresholds than the control group but similar pain thresholds for the electrical current. Likewise, pain sensitivity for tonic heat stimulation also did not differ between groups. With regard to our main hypotheses, we found that CPM inhibition neither differed between migraineurs and healthy volunteers nor varied over the menstrual cycle. Our findings suggest that CPM inhibition is not altered in female migraineurs; thus, it is questionable whether CPM really plays a role in the development of migraine or whether migraine leads to a dysfunctional CPM inhibition.

Transcutaneous electric nerve stimulation in trigeminal neuralgia: A review of literature

Trigeminal neuralgia typically involves nerves supplying teeth, jaws and face of mostly older females around 35 years. A thorough investigation and proper diagnosis is a must prior to treatment for which investigations like computed tomography and magnetic resonance imaging should be done to rule out other systemic pathology. A proper history and multidisciplinary examination is a must for the same. The surgeon should have a thorough knowledge of both odontogenic and non odontogenic cause of pain to confirm the diagnosis and a diagnostic block has been enough in case of no other systemic pathology. Though the etiology is usually obscure, different treatment modalities have been tried for it viz. medicinal treatment, alcohol injection, peripheral neurectomy, rhizotomy and microvascular decompression etc. Transcutaneous electric nerve stimulation (TENS) is a safer, cheaper and promising option for management of neuralgic patients as an adjunct with the drugs used like baclofen or carbamazepine thereby reducing the dose of the drugs taken and minimizing the side-effects of the drugs. The analgesic mechanism of TENS involves gate control theory, physiological block and endogenous pain inhibitory systems. It is a noninvasive and safer adjunct to medical treatment in chronic neuralgic pain, economical and easy for both the doctor and the patient. The reduction of pain can be assessed by patient's verbal response as comparatively objective scale like visual analog scale or McGill's questionnaire could not be clinically applied. TENS cannot be considered as a sole remedy in chronic pain conditions, but as an adjunct whose effectiveness needs a continuous follow-up.

An Endogenous Pain Control System is Altered in Subjects with Interstitial Cystitis

Multiple studies have demonstrated that in healthy subjects, painful stimuli applied to one part of the body inhibit pain sensation in other parts of the body, a phenomenon referred to as conditioned pain modulation. Conditioned pain modulation is related to the presence of endogenous pain control systems. Studies have demonstrated deficits in conditioned pain modulation associated inhibition in many but not all chronic pain disorders. In this study we determine whether conditioned pain modulation is altered in subjects with interstitial cystitis/bladder pain syndrome. Female subjects with and without the diagnosis of interstitial cystitis/bladder pain syndrome were studied psychophysically using quantitative cutaneous thermal, forearm ischemia and ice water immersion tests. Conditioned pain modulation was assessed by quantifying the effects of immersion of the hand in ice water (conditioning stimulus) on threshold and tolerance of cutaneous heat pain (test stimulus) applied to the contralateral lower extremity. The conditioned pain modulation responses of the subjects with interstitial cystitis/bladder pain syndrome were statistically different from those of healthy control subjects for cutaneous thermal threshold and tolerance measures. Healthy control subjects demonstrated statistically significant increases in thermal pain tolerance whereas subjects with the diagnosis of interstitial cystitis/bladder pain syndrome demonstrated statistically significant reductions in thermal pain tolerance. An endogenous pain inhibitory system normally observed with conditioned pain modulation was altered in subjects with interstitial cystitis/bladder pain syndrome. This finding identifies interstitial cystitis/bladder pain syndrome as similar to several other chronic pain disorders such as fibromyalgia and irritable bowel syndrome, and suggests that a deficit in endogenous pain inhibitory systems may contribute to such chronic pain disorders.

Central Sensitization and Altered Central Pain Processing in Chronic Low Back Pain

The purpose of this narrative review is to analyze the available literature concerning central sensitization and altered central pain processing in patients with chronic low back pain (LBP). Literature was screened using several electronic search databases. Additional literature was obtained by reference tracking and expert consultation. Studies evaluating central pain processing in conservatively treated patients with chronic LBP were included. Results of studies examining the responsiveness to various stimuli in patients with chronic LBP are conflicting. Some studies in patients with chronic LBP have demonstrated exaggerated pain responses after sensory stimulation of locations outside the painful region, while other studies report no differences between patients and healthy subjects. Studies examining the integrity of the endogenous pain inhibitory systems report unaltered activity of this descending inhibitory system. In contrast, studies analyzing brain structure and function in relation to (experimentally induced) pain provide preliminary evidence for altered central nociceptive processing in patients with chronic LBP. Finally, also psychosocial characteristics, such as inappropriate beliefs about pain, pain catastrophizing, and/or depression may contribute to the mechanisms of central sensitization. It tempting to speculate that ongoing nociception is associated with cortical and subcortical reorganization and may play an important role in the process of the chronification of LBP. Future prospective research should explore to what extent these changes are reversible and if this reversibility is associated with improved functioning of patients.

Asymmetric pain processing in Parkinson's disease

Reduced endogenous pain inhibition, as part of the degenerative process, is presumed to be the mechanism underlying the common presence of pain in patients with Parkinson's disease (PD). The present study aimed to assess an endogenous pain inhibitory system in PD using the conditioned pain modulation paradigm. Twenty-six predominantly unilateral PD patients and 19 controls underwent psychophysical pain assessment before and after patients' morning dopaminergic medication. An unexpected increase in several parameters of pain perception for PD patients was found after dopaminergic medication (e.g. for 49°C noxious heat stimulation an increase from 70.6±4.0 to 77.6±4.0 on the numerical pain scale, P<0.001). This increase was seen in patients with predominantly left-sided PD, regardless of the stimulated side (for 49°C noxious heat stimulation, predominantly left-sided PD patients, pain perception increased from 73.5±6.8 to 85.0±6.8, P<0.001, whereas predominantly right-sided PD patients did not show a significant increase, 68.3±6.8 to 70.4±6.5, P=0.777). Baseline efficiency of conditioned pain modulation inversely correlated with age at disease onset (r=-0.522; P=0.009) and disease severity (Unified PD Rating Scale, r=0.447; P=0.032) but did not differ between patients and controls. Increased sensory response causing hyperalgesia occurs after dopaminergic medication in patients with predominantly left-sided PD.

Alterations in endogenous pain modulation in endurance athletes: An experimental study using quantitative sensory testing and the cold-pressor task

There is evidence for long-term alterations in pain tolerance among athletes compared with normally active controls. However, scientific data on pain thresholds in this population are inconsistent, and the underlying mechanisms for the differences remain unclear. Therefore, we assessed differences and similarities in pain perception and conditioned pain modulation (CPM) at rest in endurance athletes and normally active controls.The standardised quantitative sensory testing protocol (QST) of the ‘German-Research-Network-on-Neuropathic-Pain’ was used to obtain comprehensive profiles on somatosensory functions. The protocol consisted of thermal and mechanical detection as well as pain thresholds, vibration thresholds, and pain sensitivity to sharp and blunt mechanical stimuli. CPM (the diffuse-noxious-inhibitory-control-like effect) was measured using 2 tonic heat pain test stimuli (at the temperature exceeding a subjective pain rating of 50/100) separated by a 2-min cold-pressor task (CPM-TASK; conditioning stimulus). Pain ratings were measured with a numerical rating scale. Endurance capacity was validated by assessment of maximum oxygen uptake (VO2max). Participants included 25 pain-free male endurance athletes (VO2max>60mL/min∗kg) and 26 pain-free normally active controls (VO2max<45mL/min∗kg) matched based on age and body mass index.Athletes were significantly less sensitive to mechanical pain but showed higher sensitivity to vibration (P<0.05). In athletes, CPM was significantly less activated by the conditioning stimuli (P<0.05) when compared with normally active controls.Our data show that somatosensory processing in athletes differs in comparison with controls, and suggest that the endogenous pain inhibitory system may be less responsive. This finding may explain the paradoxical propensity of athletes to develop chronic widespread pain.

Serotonergic neural links from the dorsal raphe nucleus modulate defensive behaviours organised by the dorsomedial hypothalamus and the elaboration of fear-induced antinociception via locus coeruleus pathways

Decrease of γ-aminobutyric acid (GABA)-mediated neurotransmission in the dorsomedial hypothalamus (DMH) evokes instinctive fear-like responses. The aim of the present study was to investigate the involvement of the serotonin (5-HT)- and norepinephrine-mediated pathways of the endogenous pain inhibitory system, including the dorsal raphe nucleus (DRN) and the locus coeruleus (LC), in the defensive responses and antinociceptive processes triggered by the blockade of GABAergic receptors in the DMH. The intra-hypothalamic microinjection of the GABAA receptor antagonist bicuculline (40 ng/200 nL) elicited elaborate defensive behaviours interspersed with exploratory responses. This escape behaviour was followed by significantly increased pain thresholds, a phenomenon known as fear-induced antinociception. Furthermore, at 5 and 14 days after DRN serotonin-containing neurons were damaged using the selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), the frequency and duration of alertness and escape behaviour evoked by the GABAA receptor blockade in the DMH decreased, as well as fear-induced antinociception. Pre-treatment with the non-selective 5-HT receptor antagonist methysergide, the 5-HT2A/2C receptor antagonist ketanserin and the 5-HT2A receptor selective antagonist R-96544 in the LC also decreased fear-induced antinociception, without significant changes in the expression of defensive behaviours. These data suggest that the serotonergic neurons of the DRN are directly involved in the organisation of defensive responses as well as in the elaboration of the innate fear-induced antinociception. However, serotonin-mediated inputs from the NDR to the LC modulate only fear-induced antinociception and not the defensive behaviours evoked by GABAA receptor blockade in the DMH.