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Background and aims Pain-related fear and its subsequent generalization is key to the development and maintenance of chronic pain disability. Research has shown that pain-related fear acquired through classical conditioning generalizes following a gradient, that is, novel movements that are proprioceptively similar to the original pain-associated movement elicit more fear. Studies suggest that classical conditioning can also modulate pain and conditioned fear seems to mediate this effect. However, it remains uninvestigated whether this is also the case for generalized fear. Methods In a voluntary joystick movement paradigm, one movement (conditioned stimulus; CS+) was followed by pain (pain-US), and another was not (CS-). Generalization to five novel movements (generalization stimuli; GSs) with varying levels of similarity to the CSs was tested when paired with an at-pain-threshold intensity stimulus (threshold-USs). We collected self-reported fear and pain, as well as eyeblink startle responses as an additional index of conditioned fear. Results Results showed a fear generalization gradient in the ratings, but not in the startle measures. The data did not support the idea that fear generalization mediates spreading of pain. Conclusions Despite the lack of effects in the current study, this is a promising novel approach to investigate pain modulation in the context of chronic pain. Implications This study replicates the finding that pain-related fear spreads selectively towards movements that are proprioceptively more similar to the original pain-eliciting movement. Although results did not support the idea that such generalized fear mediates spreading of pain, the study provides a promising approach to investigate pain modulation by pain-associated movements.
Learn More >Background and aims Preclinical studies have reported that activation of peripheral γ-aminobutyric acid A (GABAA) receptors may result in analgesia. The current study was conducted in young healthy men (n = 30) and women (n = 28) to determine whether injections of GABA into the masseter muscle reduce pain in a sex-related manner. Methods The effect of injection of GABA alone, or in combination with the non-inflammatory algogen glutamate, was assessed in two separate studies. Lorazepam, a positive allosteric modulator of the GABAA-receptor, was co-injected with GABA in both studies to explore the role of this receptor in muscle pain responses of healthy human volunteers. Masticatory muscle mechanical pain intensity was recorded on an electronic visual analogue scale (VAS) while muscle pain sensitivity was assessed by determining the pressure pain threshold (PPT), tolerance and maximal jaw opening (MJO) of the subjects prior to, and again after the various intramuscular injections. Results Intramuscular injection of GABA alone was reported to be significantly more painful, in a concentration related manner, than saline control injections, and this pain was further increased by co-injection of lorazepam with GABA. Co-injection of GABA with glutamate was found to significantly increase glutamate-evoked masseter muscle pain in men, but not in women. There was no effect of injections of either GABA alone, or GABA with glutamate, on PPT, tolerance or maximum jaw opening. Conclusions Injection of GABA into the human masseter muscle appears to excite nociceptors to produce muscle pain without a longer term effect on mechanical pain sensitivity in the muscle. The findings suggest that GABA-mediated pain in humans is produced through peripheral GABAA receptor activation. The mechanism underlying the sex-related difference in the effect of GABA on glutamate-evoked muscle pain was speculated to be due to a methodological artifact. Implications This study was designed to detect analgesic rather than algesic effects of peripherally administered GABA, and as a result, the concentration of glutamate chosen for injection was close to the maximal pain response for healthy women, based on previously determined pain-concentration response relationships for glutamate. This may explain the finding of greater pain in men than women, when GABA and glutamate were co-injected. Overall, the findings suggest that activation of peripheral GABAA receptors in human masticatory muscle produces pain, possibly due to depolarization of the masticatory muscle afferent fibers.
Learn More >Background Acute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia). Critical role for immune system cells in chronic pain Preclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain. Immune system reactions to peripheral nerve injuries At the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG. Immune system mechanisms in the central nervous system In the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms. Conclusions and implications Definition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.
Learn More >Naringenin (2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one is a natural flavonoid found in fruits from the citrus family. Since (2S)-Naringenin is known to racemize, its bioactivity might be related to one or both enantiomers. Computational studies predicted that (2R)-Naringenin may act on voltage-gated ion channels, particularly the N-type calcium channel (CaV2.2) and the NaV1.7 sodium channel – both key for pain signaling. Here we set out to identify the possible mechanism of action of Naringenin. Naringenin inhibited depolarization-evoked Ca2+ influx in acetylcholine-, ATP- and capsaicin-responding rat dorsal root ganglion (DRG) neurons. This was corroborated in electrophysiological recordings from DRG neurons. Pharmacological dissection of each of the voltage-gated Ca2+ channels subtypes could not pinpoint any selectivity of Naringenin. Instead, Naringenin inhibited NaV1.8-dependent, tetrodotoxin (TTX)-resistant while sparing tetrodotoxin sensitive (TTX-S) voltage-gated Na+ channels as evidenced by the lack of further inhibition by the NaV1.8 blocker A-803467. The effects of the natural flavonoid were validated ex vivo in spinal cord slices where Naringenin decreased both the frequency and amplitude of sEPSC recorded in neurons within the substantia gelatinosa. The antinociceptive potential of Naringenin was evaluated in male and female mice. Naringenin had no effect on the nociceptive thresholds evoked by heat. Naringenin's reversed allodynia was in mouse models of post-surgical and neuropathic pain. Here, driven by a call by the NCCIH's strategic plan to advance fundamental research into basic biological mechanisms of action of natural products, we advance the antinociceptive potential of the flavonoid Naringenin.
Learn More >Background and aims Cervicogenic headache (CEH) is a debilitating condition and analgesics have limited effect. Percutaneous cryoneurolysis is thus still in use although the clinical evidence is lacking. We present a randomized, controlled study to assess the clinical efficacy of cryoneurolysis compared with a corticosteroid combined with a local anaesthetic. Methods In a university-based outpatient pain clinic we performed a randomized, double blinded, comparative study with an 18-week follow-up. After positive diagnostic test blocks 52 eligible patients were randomly allocated in a ratio of 3:2, 31 participants to occipital cryoneurolysis and 21 participants to injections of 1 mL methylprednisolone 40 mg/mL (Depo-Medrol®) combined with 1 mL bupivacaine 5 mg/mL. Results We observed a significant pain reduction of more than 50% in both treatment groups, slightly improved neck function and reduced number of opioid consumers. After 6-7-weeks, however, pain intensity increased gradually, but did not reach baseline within 18 weeks. Although cryoneurolysis provided a more prolonged effect, the group differences did not reach statistical significance. Health related quality of life and psychological distress improved minimally. A large number reported minor and transient side effects, but we found no significant group differences. After 18 weeks, 29% rated the headache as much improved, and 12 (24%) somewhat improved, but a large proportion (78%) reported need for further intervention/treatment. Conclusions Cryoneurolysis provided substantial, but temporary pain relief, and the effect was not significantly different from injections of a corticosteroid combined with a local anaesthetic. Participants were selected by a single test block, and the neurolytic procedure was guided by anatomical landmarks and nerve stimulation. A stricter patient selection and an ultrasound-guided technique might have improved the results. Cryoneurolysis provides temporary pain relief not significantly superior to corticosteroid injection, and the results question the value of occipital cryoneurolysis for a chronic pain condition like CEH. Implications Occipital cryoneurolysis may be considered when non-invasive treatments appear insufficient, but only for patients who have responded substantially to test blocks. A risk of local scar and neuroma formation by repeated cryoneurolysis, leading to neuropathic pain has been discussed by other researchers.
Learn More >As professional health care personnel we are well educated in anatomy, physiology, clinical medicine and so forth. Our patients present with various symptoms and signs that we use this knowledge to diagnose and treat. But sometimes the patient case contradicts our knowledge. Since the patient is the terrain and our knowledge is the map, these patient cases are anomalies that give us the opportunity to update our maps. One such anomaly is how time restricted amnesia can improve or even eradicate an underlying chronic pain condition and eliminate the patient's dependence on daily opioid consumption. In this short communication I will use amnesia as a starting point to briefly review chronic pain from a learning and memory perspective. I will introduce, for many readers, new concepts like degeneracy and criticality, and together with more familiar concepts like habits and brain network activity, we will end with overarching principles for how chronic pain treatment in general can be crafted and individualized almost independently of the chronic pain condition at hand. This introductory article is followed by a review series that elaborates on the fundamental biological principles for chronic pain, treatment options, and testing the theory with real world data.
Learn More >The non-selective activation of central and peripheral opioid receptors is a major shortcoming of currently available opioids. Targeting peripheral opioid receptors is a promising strategy to preclude side effects. Recently, we showed that fentanyl-derived μ-opioid receptor (MOR) agonists with reduced acid dissociation constants (pK) due to introducing single fluorine atoms produced injury-restricted antinociception in rat models of inflammatory, postoperative and neuropathic pain. Here, we report that a new double-fluorinated compound (FF6) and fentanyl show similar pK, MOR affinity and [S]-GTPγS binding at low and physiological pH values. In vivo, FF6 produced antinociception in injured and non-injured tissue, and induced sedation and constipation. The comparison of several fentanyl derivatives revealed a correlation between pK values and pH-dependent MOR activation, antinociception and side effects. An opioid ligand's pK value may be used as discriminating factor to design safer analgesics.
Learn More >Background and aims Persons with chronic widespread pain (CWP) have poor medical outcomes and increased mortality. But there are no universally accepted criteria for CWP or of methods to assess it. The most common criteria come from the 1990 American College of Rheumatology (ACR) fibromyalgia (FM) criteria, but that method (WP1990) can identify CWP with as few as three pain sites, and in subjects with wide differences in illness severity. Recently, to correct WP1990 deficiencies, the 2016 fibromyalgia criteria provided a modified CWP definition (WP2016) by dividing the body into five regions of three pain sites each and requiring a minimum of four regions of pain. Although solving the geographic problem of pain distribution, the problem of just how many pain sites (pain diffuseness) are required remained a problem, as WP2016 required as few as four painful sites. To better characterize CWP, we compared four CWP definitions with respect to symmetry, extent of pain sites and association with clinical severity variables. Methods We characterized pain in 40,960 subjects, including pain at 19 individual sites and five pain regions, and calculated the widespread pain index (WPI) and polysymptomatic distress scales (PDS) from epidemiology, primary care and rheumatology databases. We developed and evaluated a new definition for CWP, (WP2019), defined as pain in four or five regions and a pain site score of at least seven of 15 sites. We also tested a definition based on the number of painful sites (WPI ≥ 7). Results In rheumatology patients, WP1990 and WPI ≥ 7 classified patients with <4 regions as WSP. CWP was noted in 51.3% by WP1990, 41.7% by WP2016, 37.6% of WPI ≥ 7 and 33.9% by WP2019. 2016 FM criteria was satisfied in WP1990 (51.1%), WP2016 (63.3%), WPI ≥ 7 (69.0%) and WP2019 (76.6%). WP2019 positive patients had more severe clinical symptoms compared with WP1990, WP2016 and WPI ≥ 7, and similar to but less than FM 2016 positive patients. In stepwise fashion, scores for functional disability, visual analog scale fatigue and pain, WPI, polysymptomatic distress score and Patient Health Questionnaire 15 (PHQ-15) worsened from WP1990 through WP2016, WPI ≥ 7 and WP2019. Conclusions WP2019 combines the high WPI scores of WPI ≥ 7 and the symmetry of WP2016, and is associated with the most abnormal clinical scores. The WP1990 does not appear to be an effective measure. We suggest that CWP can be better defined by combining 4-region pain and a total pain site score ≥7 (WP2019). This definition provides a simple, unambiguous measure that is suitable for clinical and research use as a standalone diagnosis that is integrated with fibromyalgia definitions. Implications Definitions of CWP in research and clinic care are arbitrary and have varied, and different definitions of CWP identify different sets of patients, making a universal interpretation of CWP uncertain. In addition, CWP is a mandatory component of some fibromyalgia criteria. Our study provides quantitative data on the differences between CWP definitions and their criteria, allowing better understanding of research results and a guide to the use of CWP in clinical care.
Learn More >It has been suggested that alterations in inflammation molecules maintain chronic pain although little is known about how these factors influence homeostatic and inflammatory events in common chronic pain conditions. Nonpharmacological interventions might be associated with alterations in inflammation markers in blood. This study of patients with chronic pain investigates whether an interdisciplinary multimodal rehabilitation program (IMMRP) was associated with significant alterations in the plasma pattern of 68 cytokines/chemokines 1 year after rehabilitation and whether such changes were associated with clinical changes. Blood samples and self-reports of pain, psychological distress, and physical activity of 25 complex chronic pain patients were collected pre-IMMRP and at 12-month follow-up. Analyses of inflammatory proteins (cytokines/chemokines/growth factors) were performed directly in plasma using the multiplex immunoassay technology Meso Scale Discovery. This explorative pilot study found that 12 substances, mainly pro-inflammatory, decreased after IMMRP. In two other relatively small IMMRP studies, four of these proinflammatory markers were also associated with decreases. The pattern of cytokines/chemokines pre-IMMRP was associated with changes in psychological distress but not with pain or physical activity. The present study cannot impute cause and effect. These results together with the results of the two previous IMMRP studies suggest that there is a need for larger and more strictly controlled studies of IMMRP with respect to inflammatory markers in blood. Such studies need to consider responders/non-responders, additional therapies, involved pain mechanisms and diagnoses. This and the two other studies open up for developing biologically measurable outcomes from plasma. Such biomarkers will be an important tool for further development of IMMRP and possibly other treatments for patients w ith chronic pain.
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