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Prehabilitation programs have led to improved postoperative outcomes in several surgical contexts, but there are presently no guidelines for the prehabilitation phase before lumbar fusion surgery.
Learn More >Itch is a distinct aversive sensation that elicits a strong urge to scratch. Despite recent advances in our understanding of the peripheral basis of itch, we know very little regarding how central neural circuits modulate acute and chronic itch processing. Here we establish the causal contributions of defined periaqueductal gray (PAG) neuronal populations in itch modulation in mice. Chemogenetic manipulations demonstrate bidirectional modulation of scratching by neurons in the PAG. Fiber photometry studies show that activity of GABAergic and glutamatergic neurons in the PAG is modulated in an opposing manner during chloroquine-evoked scratching. Furthermore, activation of PAG GABAergic neurons or inhibition of glutamatergic neurons resulted in attenuation of scratching in both acute and chronic pruritis. Surprisingly, PAG GABAergic neurons, but not glutamatergic neurons, may encode the aversive component of itch. Thus, the PAG represents a neuromodulatory hub that regulates both the sensory and affective aspects of acute and chronic itch.
Learn More >Our understanding of the biology of pain is limited by our ignorance about its evolution. We know little about how states in other species showing various degrees of apparent similarity to human pain states are related to human pain, or how the mechanisms essential for pain-related states evolved. Nevertheless, insights into the evolution of mechanisms and behaviour important for pain are beginning to emerge from wide-ranging investigations of cellular mechanisms and behavioural responses linked to nociceptor activation, tissue injury, inflammation and the environmental context of these responses in diverse species. In February 2019, an unprecedented meeting on the evolution of pain hosted by the Royal Society brought together scientists from disparate fields who investigate nociception and pain-related behaviour in crustaceans, insects, leeches, gastropod and cephalopod molluscs, fish and mammals (primarily rodents and humans). Here, we identify evolutionary themes that connect these research efforts, including adaptive and maladaptive features of pain-related behavioural and neuronal alterations-some of which are quite general, and some that may apply primarily to humans. We also highlight major questions, including how pain should be defined, that need to be answered as we seek to understand the evolution of pain. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Astrocytes are critical for maintaining the homeostasis of the CNS. Increasing evidence suggests that a number of neurological and neuropsychiatric disorders, including chronic pain, may result from astrocyte 'gliopathy'. Indeed, in recent years there has been substantial progress in our understanding of how astrocytes can regulate nociceptive synaptic transmission via neuronal-glial and glial-glial cell interactions, as well as the involvement of spinal and supraspinal astrocytes in the modulation of pain signalling and the maintenance of neuropathic pain. A role of astrocytes in the pathogenesis of chronic itch is also emerging. These developments suggest that targeting the specific pathways that are responsible for astrogliopathy may represent a novel approach to develop therapies for chronic pain and chronic itch.
Learn More >Mechanical itch is a desire to scratch due to light mechanical stimuli. In this issue of Neuron, Pan et al. (2019) identify a feedforward inhibition circuit in the spinal cord dorsal horn that processes mechanical itch as well as spontaneous itch.
Learn More >Acute and persistent post-traumatic headache are often debilitating consequences of traumatic brain injury. Underlying physiological mechanisms of post-traumatic headache and its persistence remain unknown, and there are currently no approved therapies for these conditions. Post-traumatic headache often presents with a migraine-like phenotype. As calcitonin-gene related peptide promotes migraine headache, we explored the efficacy and timing of intervention with an anti- calcitonin-gene related peptide monoclonal antibody in novel preclinical models of acute post-traumatic headache and persistent post-traumatic headache following a mild traumatic brain injury event in mice.
Learn More >Voltage-gated sodium channel Nav1.9 is a threshold channel that regulates action potential firing. Nav1.9 is preferentially expressed in myenteric neurons, and small-diameter dorsal root ganglion (DRG) and trigeminal ganglion neurons including nociceptors. Recent studies have demonstrated a monogenic Mendelian link of Nav1.9 to human pain disorders. Gain-of-function variants in Nav1.9, which cause smaller depolarizations of RMP, have been identified in patients with familial episodic pain type 3 (FEPS3) and the more common pain disorder small fiber neuropathy. To explore the phenotypic spectrum of Nav1.9 channelopathy, here we report a new Nav1.9 mutation, N816K, in a child with early-onset episodic pain in both legs, episodic abdominal pain, and chronic constipation. Sequencing of further selected pain genes was normal. N816K alters a residue at the N-terminus of loop 2, proximal to the cytoplasmic terminus of transmembrane segment 6 in domain II. Voltage-clamp recordings demonstrate that Nav1.9-N816K significantly increases current density and hyperpolarizes voltage-dependence of activation by 10 mV, enabling a larger window current. Current-clamp recordings in DRG neurons shows that N816K channels depolarize RMP of small DRG neurons by 7 mV, reduce current threshold of firing an action potential and render DRG neurons hyperexcitable. Taken together these data demonstrate gain-of-function attributes of the newly described N816K mutation at the channel and cellular levels, which are consistent with a pain phenotype in the carrier of this mutation.
Learn More >Optogenetics provide a potential alternative approach to the treatment of chronic pain, in which complex pathology often hampers efficacy of standard pharmacological approaches. Technological advancements in the development of thin, wireless, and mechanically flexible optoelectronic implants offer new routes to control the activity of subsets of neurons and nerve fibers . This study reports a novel and advanced design of battery-free, flexible, and lightweight devices equipped with one or two miniaturized LEDs, which can be individually controlled in real time. Two proof-of-concept experiments in mice demonstrate the feasibility of these devices. First, we show that blue-light devices implanted on top of the lumbar spinal cord can excite channelrhodopsin expressing nociceptors to induce place aversion. Second, we show that nocifensive withdrawal responses can be suppressed by green-light optogenetic (Archaerhodopsin-mediated) inhibition of action potential propagation along the sciatic nerve. One salient feature of these devices is that they can be operated via modern tablets and smartphones without bulky and complex lab instrumentation. In addition to the optical stimulation, the design enables the simultaneously wireless recording of the temperature in proximity of the stimulation area. As such, these devices are primed for translation to human patients with implications in the treatment of neurological and psychiatric conditions far beyond chronic pain syndromes.
Learn More >Recapitulating human disease pathophysiology using genetic animal models is a powerful approach to enable mechanistic understanding of genotype-phenotype relationships for drug development. NaV1.7 is a sodium channel expressed in the peripheral nervous system with strong human genetic validation as a pain target. Efforts to identify novel analgesics that are non-addictive, resulted in industry exploration of a class of sulfonamide compounds that bind to the fourth voltage-sensor domain of NaV1.7. Due to sequence differences in this region, sulfonamide blockers generally are potent on human but not rat NaV1.7 channels. To test sulfonamide-based chemical matter in rat models of pain, we generated a humanized NaV1.7 rat expressing a chimeric NaV1.7 protein containing the sulfonamide-binding site of the human gene sequence as a replacement for the equivalent rat sequence. Unexpectedly, upon transcription the human insert was spliced out, resulting in a premature stop codon. Using a validated antibody, NaV1.7 protein was confirmed to be lost in the brainstem, dorsal root ganglia (DRG), sciatic nerve and gastrointestinal tissue but not in nasal turbinates or olfactory bulb in rats homozygous for the knock-in allele (HOM-KI). HOM-KI rats exhibited normal intraepidermal nerve fiber density with reduced tetrodotoxin-sensitive current density and action potential firing in small diameter DRG neurons. HOM-KI rats did not exhibit nociceptive pain responses in hot plate or capsaicin-induced flinching assays and did not exhibit neuropathic pain responses following spinal nerve ligation. Consistent with expression of chimeric NaV1.7 in olfactory tissue, HOM-KI rats retained olfactory function. This new genetic model highlights the necessity of NaV1.7 for pain behavior in rats and indicates that sufficient inhibition of NaV1.7 in humans may reduce pain in neuropathic conditions. Due to preserved olfactory function, this rat model represents an alternative to global NaV1.7 knockout mice that require time-intensive hand feeding during early postnatal development.
Learn More >Avoidance is considered key in the development of chronic pain. However, little is known about how avoidance behaviour subsequently affects pain-related fear and pain. We investigated this using a robotic arm reaching avoidance task to investigate this. In a between-subjects design both Experimental Group (n=30) and Yoked Control Group (n=30) participants perform either of three movement trajectories (T1-T3) to reach a target location. During acquisition, only participants of the Experimental Group could partially or fully avoid a painful electrocutaneous stimulus by choosing the intermediate trajectory (T2; 50% reinforcement) or the longest trajectory (T3; 0% reinforcement) versus the shortest trajectory (T1: 100% reinforcement). After acquisition, contingencies changed (all trajectories 50% reinforced), and the acquired avoidance behaviour no longer effectively prevented pain from occurring. The Yoked Control Group received the same reinforcement schedule as the Experimental Group irrespective of their behaviour. When avoidance behaviour became ineffective for the Experimental Group, pain-related fear increased for the previously safe(r) trajectories (T2 and T3) and remained the same for T1, whereas pain threshold and tolerance declined. For the Yoked Group, pain-related fear increased for all trajectories. The Experimental Group persisted in emitting avoidance behaviour following the contingency change, albeit at a lower frequency than during acquisition. PERSPECTIVE: Results indicate participants become more afraid of and sensitive to pain, when previously acquired avoidance is no longer effective. Also, participants continue to show avoidance behaviour despite it being not adaptive anymore. These findings suggest that ineffective avoidance may play role in the maintenance and development of chronic pain.
Learn More >Vagus nerve stimulation (VNS) is a common treatment for medically intractable epilepsy, but response rates are highly variable, with no preoperative means of identifying good candidates. This study aimed to predict VNS response using structural and functional connectomic profiling.
Learn More >ICHD-3 criteria for chronic migraine (CM) include a mixture of migraine and tension-type-like headaches and do not account for patients who have a high frequency of migraine but no other headaches.
Learn More >Nociceptors, i.e. sensory neurons tuned to detect noxious stimuli, are found in numerous phyla of the Animalia kingdom and are often polymodal, responding to a variety of stimuli, e.g. heat, cold, pressure and chemicals, such as acid. Owing to the ability of protons to have a profound effect on ionic homeostasis and damage macromolecular structures, it is no wonder that the ability to detect acid is conserved across many species. To detect changes in pH, nociceptors are equipped with an assortment of different acid sensors, some of which can detect mild changes in pH, such as the acid-sensing ion channels, proton-sensing G protein-coupled receptors and several two-pore potassium channels, whereas others, such as the transient receptor potential vanilloid 1 ion channel, require larger shifts in pH. This review will discuss the evolution of acid sensation and the different mechanisms by which nociceptors can detect acid. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Animal behaviours are affected not only by inherited genes but also by environmental experiences. For example, in both rats and humans, stressful early-life events such as being reared by an inattentive mother can leave a lasting trace and affect later stress response in adult life. This is owing to a chemical trace left on the chromatin attributed to so-called epigenetic mechanisms. Such an epigenetic trace often has consequences, sometimes long-lasting, on the functioning of our genes, thereby allowing individuals to rapidly adapt to a new environment. One gene under such epigenetic control is , the gene that encodes the protein FKPB51, a crucial regulator of the stress axis and a significant driver of chronic pain states. In this article, we will discuss the possibility that exposure to stress could drive the susceptibly to chronic pain epigenetic modifications of genes within the stress axis such as . The possibility that such modifications, and therefore, the susceptibility to chronic pain, could be transmitted across generations in mammals and whether such mechanisms may be evolutionarily conserved across phyla will also be debated. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Evolutionary models of chronic pain are relatively undeveloped, but mainly concern dysregulation of an efficient acute defence, or false alarm. Here, a third possibility, mismatch with the modern environment, is examined. In ancestral human and free-living animal environments, survival needs urge a return to activity during recovery, despite pain, but modern environments allow humans and domesticated animals prolonged inactivity after injury. This review uses the research literature to compare humans and other mammals, who share pain neurophysiology, on risk factors for pain persistence, behaviours associated with pain, and responses of conspecifics to behaviours. The mammal populations studied are mainly laboratory rodents in pain research, and farm and companion animals in veterinary research, with observations of captive and free-living primates. Beyond farm animals and rodent models, there is virtually no evidence of chronic pain in other mammals. Since evidence is sparse, it is hard to conclude that it does not occur, but its apparent absence is compatible with the mismatch hypothesis. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >In order to survive, animals must avoid injury and be able to detect potentially damaging stimuli via nociceptive mechanisms. If the injury is accompanied by a negative affective component, future behaviour should be altered and one can conclude the animal experienced the discomfort associated with pain. Fishes are the most successful vertebrate group when considering the number of species that have filled a variety of aquatic niches. The empirical evidence for nociception in fishes from the underlying molecular biology, neurobiology and anatomy of nociceptors through to whole animal behavioural responses is reviewed to demonstrate the evolutionary conservation of nociception and pain from invertebrates to vertebrates. Studies in fish have shown that the biology of the nociceptive system is strikingly similar to that found in mammals. Further, potentially painful events result in behavioural and physiological changes such as reduced activity, guarding behaviour, suspension of normal behaviour, increased ventilation rate and abnormal behaviours which are all prevented by the use of pain-relieving drugs. Fish also perform competing tasks less well when treated with a putative painful stimulus. Therefore, there is ample evidence to demonstrate that it is highly likely that fish experience pain and that pain-related behavioural changes are conserved across vertebrates. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Enormous progress in understanding the mechanisms that mediate pain can be augmented by an evolutionary medicine perspective on how the capacity for pain gives selective advantages, the trade-offs that shaped the mechanisms, and evolutionary explanations for the system's vulnerability to excessive and chronic pain. Syndromes of deficient pain document tragically the utility of pain to motivate escape from and avoidance of situations causing tissue damage. Much apparently excessive pain is actually normal because the cost of more pain is often vastly less than the cost of too little pain (the smoke detector principle). Vulnerability to pathological pain may be explained in part because natural selection has shaped mechanisms that respond adaptively to repeated tissue damage by decreasing the pain threshold and increasing pain salience. The other half of an evolutionary approach describes the phylogeny of pain mechanisms; the apparent independence of different kinds of pain is of special interest. Painful mental states such as anxiety, guilt and low mood may have evolved from physical pain precursors. Preliminary evidence for this is found in anatomic and genetic data. Such insights from evolutionary medicine may help in understanding vulnerability to chronic pain. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Injury to sensory neurons causes an increase in the excitability of these cells leading to enhanced action potential generation and a lowering of spike threshold. This type of sensory neuron plasticity occurs across vertebrate and invertebrate species and has been linked to the development of both acute and persistent pain. Injury-induced plasticity in sensory neurons relies on localized changes in gene expression that occur at the level of mRNA translation. Many different translation regulation signalling events have been defined and these signalling events are thought to selectively target subsets of mRNAs. Recent evidence from mice suggests that the key signalling event for nociceptor plasticity is mitogen-activated protein kinase-interacting kinase (MNK) -mediated phosphorylation of eukaryotic translation initiation factor (eIF) 4E. To test the degree to which this is conserved in other species, we used a previously described sensory neuron plasticity model in . We find, using a variety of pharmacological tools, that MNK signalling is crucial for axonal hyperexcitability in sensory neurons from . We propose that MNK-eIF4E signalling is a core, evolutionarily conserved, signalling module that controls nociceptor plasticity. This finding has important implications for the therapeutic potential of this target, and it provides interesting clues about the evolutionary origins of mechanisms important for pain-related plasticity. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Cannabinoid-based therapies have long been used to treat pain, but there remain questions about their actual mechanisms and efficacy. From an evolutionary perspective, the cannabinoid system would appear to be highly conserved given that the most prevalent endogenous cannabinoid (endocannabinoid) transmitters, 2-arachidonyl glycerol and anandamide, have been found throughout the animal kingdom, at least in the species that have been analysed to date. This review will first examine recent findings regarding the potential conservation across invertebrates and chordates of the enzymes responsible for endocannabinoid synthesis and degradation and the receptors that these transmitters act on. Next, comparisons of how endocannabinoids modulate nociception will be examined for commonalities between vertebrates and invertebrates, with a focus on the medicinal leech . Evidence is presented that there are distinct, evolutionarily conserved anti-nociceptive and pro-nociceptive effects. The combined studies across various animal phyla demonstrate the utility of using comparative approaches to understand conserved mechanisms for modulating nociception. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Nerve injury leads to devastating and often untreatable neuropathic pain. While acute noxious sensation (nociception) is a crucial survival mechanism and is conserved across phyla, chronic neuropathic pain is considered a maladaptive response owing to its devastating impact on a patient's quality of life. We have recently shown that a neuropathic pain-like response occurs in adult . However, the mechanisms underlying this phenomenon are largely unknown. Previous studies have shown that the α2δ peripheral calcium channel subunit () is a conserved factor required for thermal pain perception. We demonstrate here that is required in peripheral sensory neurons for acute thermal responses and that it mediates nociceptive hypersensitivity in an adult model of neuropathic pain-like disease. Given that calcium channels are the main targets of gabapentinoids (pregabalin and gabapentin), we assessed if these drugs can alleviate nociceptive hypersensitivity. Our findings suggest that gabapentinoids may prevent nociceptive hypersensitivity by preserving central inhibition after nerve injury. Together, our data further highlight the similarity of some mechanisms for pain-like conditions across and validates the scientific use of neuropathic sensitization models for analgesic drug discovery. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Chronic pain is considered maladaptive by clinicians because it provides no apparent protective or recuperative benefits. Similarly, evolutionary speculations have assumed that chronic pain represents maladaptive or evolutionarily neutral dysregulation of acute pain mechanisms. By contrast, the present hypothesis proposes that chronic pain can be driven by mechanisms that evolved to reduce increased vulnerability to attack from predators and aggressive conspecifics, which often target prey showing physical impairment after severe injury. Ongoing pain and anxiety persisting long after severe injury continue to enhance vigilance and behavioural caution, decreasing the heightened vulnerability to attack that results from motor impairment and disfigurement, thereby increasing survival and reproduction (fitness). This hypothesis is supported by evidence of animals surviving and reproducing after traumatic amputations, and by complex specializations that enable primary nociceptors to detect local and systemic signs of injury and inflammation, and to maintain low-frequency discharge that can promote ongoing pain indefinitely. Ongoing activity in nociceptors involves intricate electrophysiological and anatomical specializations, including inducible alterations in the expression of ion channels and receptors that produce persistent hyperexcitability and hypersensitivity to chemical signals of injury. Clinically maladaptive chronic pain may sometimes result from the recruitment of this powerful evolutionary adaptation to severe bodily injury. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >The poor translational record of pain research has suggested to some observers that species differences in pain biology might be to blame. In this review, I consider the evidence for species similarity and differences in the pain research literature. Impressive feats of translation have been demonstrated in relation to certain genetic effects, social modulation of pain and pain memory. The degree to which pain biology in rodents predicts pain biology in humans has important implications both for evolutionary accounts of pain, but also the success of analgesic drug development going forward. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Transient receptor potential (TRP) cation channels are highly conserved, polymodal sensors which respond to a wide variety of stimuli. Perhaps most notably, TRP channels serve critical functions in nociception and pain. A growing body of evidence suggests that transient receptor potential melastatin (TRPM) and transient receptor potential ankyrin (TRPA) thermal and electrophile sensitivities predate the protostome-deuterostome split (greater than 550 Ma). However, TRPM and TRPA channels are also thought to detect modified terpenes (e.g. menthol). Although terpenoids like menthol are thought to be aversive and/or harmful to insects, mechanistic sensitivity studies have been largely restricted to chordates. Furthermore, it is unknown if TRP-menthol sensing is as ancient as thermal and/or electrophile sensitivity. Combining genetic, optical, electrophysiological, behavioural and phylogenetic approaches, we tested the hypothesis that insect TRP channels play a conserved role in menthol sensing. We found that topical application of menthol to larvae elicits a – and -dependent nocifensive rolling behaviour, which requires activation of Class IV nociceptor neurons. Further, in characterizing the evolution of TRP channels, we put forth the hypotheses that three previously undescribed TRPM channel clades (basal, αTRPM and βTRPM), as well as TRPs with residues critical for menthol sensing, were present in ancestral bilaterians. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >The social modulation of pain in humans has been neglected so far with respect to verbal as well as non-verbal communication of pain. The facial pain expression is a powerful way to communicate pain, and there are some theoretical accounts available on how social modulation may affect the encoding of the facial expression of pain. Some accounts, particularly in the pain field, are proximate explanations on the mechanisms involved, whereas an evolutionary psychology account takes a more comprehensive approach. A review of nine experimental studies revealed that in the majority of studies (6/9), social context had an effect on the facial pain expression, but results were inconsistent. Several conceptual and methodological issues are discussed which may explain these inconsistencies and could help in design of future experimental studies. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >How far back can we trace behaviour associated with pain? Behaviour is not preserved in the palaeontological record, so, for dinosaurs, we are restricted to what we can deduce from fossilized bones and tracks. This review is a thought experiment using circumstantial evidence from dinosaur fossils and from the behaviour of their extant relatives to describe probable responses of dinosaurs to serious injuries. Searches yielded 196 papers and chapters with: reports of healed serious injuries, and limping gait and injured feet in trackways; information about physiology and behaviour relevant to healing; evidence of evolutionary connections with birds and crocodilians, and their behaviour; and information about relevant aspects of evolution. Clearly, many dinosaurs survived injuries that would have seriously hampered mobility, impairing hunting or escape from predators, and affecting social interactions. Recovery from severe injuries implies pain-mediated responses. Rates of healing seem faster than for other reptiles, possibily aided by warm-bloodedness. Nesting was often communal, raising the possibility of parental and group protection for injured young. The existence of family groups, packs or herds raises the possibility of protection or feeding from pack kills. This is the first study, to our knowledge, of possible pain behaviour and responses to injury in dinosaurs. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Research in the neuroscience of pain perception and visual perception has taken contrasting paths. The contextual and the social aspects of pain judgements predisposed pain researchers to develop computational and functional accounts early, while vision researchers tended to simple localizationist or descriptive approaches first. Evolutionary thought was applied to distinct domains, such as game-theoretic approaches to cheater detection in pain research, versus vision scientists' studies of comparative visual ecologies. Both fields now contemplate current motor or decision-based accounts of perception, particularly predictive coding. Vision researchers do so without the benefit of earlier attention to social and motivational aspects of vision, while pain researchers lack a comparative behavioural ecology of pain, the normal incidence and utility of responses to tissue damage. Hybrid hypotheses arising from predictive coding as used in both domains are applied to some perplexing phenomena in pain perception to suggest future directions. The contingent and predictive interpretation of complex sensations, in such domains as 'runner's high', multiple cosmetic procedures, self-harm and circadian rhythms in pain sensitivity is one example. The second, in an evolutionary time frame, considers enhancement of primary perception and expression of pain in social species, when expressions of pain might reliably elicit useful help. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >There has been a surging interest in the putative role of peripheral growth factors in the pathophysiology of fibromyalgia, specifically in the peripheral sensitization that occurs in chronic pain disorders. This cross-sectional study set out to assess and compare brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in plasma samples from fibromyalgia patients and healthy controls. Plasma BDNF and NGF were measured in 89 fibromyalgia patients and 36 pain-free controls, and compared using ANCOVA controlling for potential confounders, as well as Bayesian methods for parameter estimation and model evaluation. BDNF and NGF levels in fibromyalgia patients did not differ from those in pain-free controls. Statistical methods were consistent, with both frequentist and Bayesian approaches leading to the same conclusions. Our study fails to replicate the finding that peripheral BDNF is altered in fibromyalgia, and instead our findings suggest that plasma levels of growth factor appear normative in fibromyalgia.
Learn More >There is growing interest in drug repositioning to find new therapeutic indications for drugs already approved for use in people. Lovastatin is an FDA approved drug that has been used clinically for over a decade as a lipid-lowering medication. While lovastatin is classically considered to act as a hydroxymethylglutaryl (HMG)-CoA reductase inhibitor, the present series of studies reveal a novel lovastatin effect, that being as a Toll-like receptor 4 (TLR4) antagonist. Lovastatin selectively inhibits lipopolysaccharide (LPS)-induced TLR4-NF-κB activation without affecting signaling by other homologous TLRs. In vitro biophysical binding and cellular thermal shift assay (CETSA) show that lovastatin is recognized by TLR4's coreceptor myeloid differentiation protein 2 (MD-2). This finding is supported by molecular dynamics simulations that lovastatin targets the LPS binding pocket of MD-2 and lovastatin binding stabilizes the MD-2 conformation. In vitro studies of BV-2 microglial cells revealed that lovastatin inhibits multiple effects of LPS, including activation of NFkB; mRNA expression of tumor necrosis factor-a, interleukin-6 and cyclo-oxygenase 2; production of nitric oxide and reactive oxygen species; as well as phagocytic activity. Furthermore, intrathecal delivery of lovastatin over lumbosacral spinal cord of rats attenuated both neuropathic pain from sciatic nerve injury and expression of the microglial activation marker CD11 in lumbar spinal cord dorsal horn. Given the well-established role of microglia and proinflammatory signaling in neuropathic pain, these data are supportive that lovastatin, as a TLR4 antagonist, may be productively repurposed for treating chronic pain.
Learn More >The current Phase 2b study aimed to evaluate the efficacy of mindfulness-based cognitive therapy for migraine (MBCT-M) to reduce migraine-related disability in people with migraine.
Learn More >To report on the benefits of noninvasive vagus nerve stimulation (nVNS) on acute vestibular migraine (VM) treatment.
Learn More >We sought to refine a screening measure for discriminating a sensitized or normal sensation pain phenotype among African American adults with sickle cell disease (SCD).
Learn More >In 2018, three calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies, erenumab, fremanezumab and galcanezumab, were approved in various parts of the world, including Europe and the US, and another, eptinezumab, is pending, for the prevention of migraine. In this article, episodic migraine treatment is reviewed, although these medicines are approved and are just as effective for chronic migraine. These new medicines usher a new phase in the preventive management of migraine with migraine-specific treatments. Data from phase III trials of CGRP pathway monoclonal antibodies have shown they are efficacious, with adverse effect rates comparable to placebo. The combination of clear efficacy and excellent tolerability will be welcome in an area where poor adherence to current preventives is common. Rimegepant, ubrogepant and lasmiditan are migraine-specific acute therapies yet to be approved by regulators. Phase III data for the respective CGRP receptor antagonists, the gepants, and the serotonin 5-HT receptor agonist, the ditan, have been positive and free of cardiovascular adverse effects. These medicines are not vasoconstrictors. When approved, they could meet the acute therapy demand of patients with cardiovascular risk factors where triptans are contraindicated. Beyond this, gepants will see the most disruptive development in migraine management in generations with medicines that can have both acute and preventive effects, the latter evidenced by data from the discontinued drug telcagepant and the early-phase drug atogepant. Moreover, one can expect no risk of medication overuse syndromes with gepants since the more patients take, the less migraines they have. During the next years, as experience with monoclonal antibodies grows in clinical practice, we can expect an evolution in migraine management to take shape. Clinicians will be able to offer treatment patients want rather than trying to fit migraineurs into therapeutic boxes for their management. Despite pessimistic susurrations of a largely addlepated form, many patients, and physicians, will welcome new options, and the challenges of new treatment paradigms, with optimism.
Learn More >It is unknown whether clinical parameters differ between migraineurs with and without first-degree family members with migraine.
Learn More >The estimation of long-standing pain in companion animals through the measurement of different dimensions impacted by pain is a fundamental requirement if pain management, and pain therapeutic development, are to advance. Although pain management in veterinary medicine has advanced considerably in the last 20 years, there is much critical work to do in the area of measurement of chronic pain. To date, most work has centered on musculoskeletal pain, and has been focused around the measurement of limb use and the development of owner-completed questionnaires, or clinical metrology instruments (CMI). Recent areas of research have extended to developing measures of activity, sensory function (quantitative sensory testing; nociceptive withdrawal reflexes), and quality of life (QoL). Across all these areas, more data on validity are needed, and studies should be extended to other painful disease states. By necessity, assessing measurement tools requires testing in field studies, which incur considerable time and expense. Facilitating these studies could be optimized with a collaborative (industry, academia and private practice) approach, and the utility of the information produced from all field studies would be enhanced by full and transparent reporting and data sharing, including data already generated by industry in the form of studies submitted to the regulatory authorities.
Learn More >There has been accumulating evidence on sex disparity in incidence, prevalence, symptomology, and burden of migraine. Several neuroimaging studies on migraine patients attempted to unravel the mechanisms of the disease, yet very few of them examined the sex-related differences. Here, we will first discuss some of the reported neuroimaging patterns that discriminate females from males in migraine. We will then re-examine the salient neuroimaging findings in migraine and discuss them in relation to sex-related influences. Finally, we will discuss some of the intriguing recent data suggesting the presence of sex-specific traits in migraineurs. These findings may have potential implications for future neuroimaging studies to identify underlying correlating patterns in the brain to (1) explain the neural basis for higher prevalence of migraine in women, and (2) better understand migraine-specific changes during different stages of life in both men and women.
Learn More >Resilience factors have been suggested as key mechanisms in the relation between symptoms and disability among individuals with chronic pain. However, there is a need to better operationalize resilience and to empirically evaluate its role and function. The present study examined psychological flexibility as a resilience factor in relation to symptoms and functioning among 252 adults with chronic pain applying for participation in a digital ACT-based self-help treatment. Participants completed measures of symptoms (pain intensity, and anxiety), functioning (pain interference and depression), as well as the hypothesized resilience factor psychological flexibility (measured as avoidance, value obstruction, and value progress). As expected, symptoms, functioning and resilience factors were significantly associated. Hierarchical linear regression analyses showed that psychological flexibility significantly contributed to the prediction of pain interference and depression when adjusting for age, pain and anxiety. Also, participants with low levels of psychological flexibility were more likely to be on sick leave. Furthermore, a series of multiple mediation analyses showed that psychological flexibility had a significant indirect effect on the relationship between symptoms and functioning. Avoidance was consistently shown to contribute to the indirect effect. Results support previous findings and suggest the importance of psychological flexibility as a resilience factor among individuals with chronic pain and anxiety.
Learn More >Chronic itch is common in the elderly patient and may be caused by a variety of known dermatologic and non-dermatologic conditions and can have a significant effect on quality of life. Age-related changes in barrier function, immunosenescence, and neuronal changes and neuropathies are common predisposing factors to chronic itch in this age group. Certain primary dermatologic conditions are more common in the elderly and can cause chronic itch. Also, co-morbid diseases particularly of the renal, hepatobiliary, or hematologic systems, psychologic conditions, or medications may contribute to chronic itch in this population. Thus, medical workup for an elderly patient with chronic itch requires special attention to the patient's medical history, current health status, and medications. Topical treatments and emollients may be recommended for elderly patients, with consideration of specific adverse effects and alternatives. Systemic medications pose a higher risk of adverse effects and many are contraindicated in the elderly for this reason. In addition, management in the elderly may be complicated by differential pharmacokinetics of medications, the presence of co-morbid health conditions, cognitive disorders, physical limitations, and polypharmacy. New and emerging treatment modalities hold promise for use in the elderly due to these special considerations.
Learn More >Although brain-derived neurotrophic factor (BDNF) is implicated in the nociceptive signaling of peripheral sensory neurons, the underlying mechanisms remain largely unknown. Here, we elucidated the effects of BDNF on the neuronal excitability of trigeminal ganglion (TG) neurons and the pain sensitivity of rats mediated by T-type Ca channels. BDNF reversibly and dose-dependently enhanced T-type channel currents through the activation of tropomyosin receptor kinase B (TrkB). Antagonism of phosphatidylinositol 3-kinase (PI3K) but not of its downstream target, the kinase AKT, abolished the BDNF-induced T-type channel response. BDNF application activated p38 mitogen-activated protein kinase (MAPK), and this effect was prevented by inhibition of PI3K but not of protein kinase A (PKA). Antagonism of either PI3K or p38 MAPK prevented the BDNF-induced stimulation of PKA activity, whereas PKA inhibition blocked the BDNF-mediated increase in T-type currents. BDNF increased the rate of action potential firing in TG neurons and enhanced the pain sensitivity of rats to mechanical stimuli. Moreover, inhibition of TrkB signaling abolished the increased mechanical sensitivity in a rat model of chronic inflammatory pain, and this effect was attenuated by either T-type channel blockade or knockdown of the channel Ca3.2. Together, our findings indicate that BDNF enhances T-type currents through the stimulation of TrkB coupled to PI3K-p38-PKA signaling, thereby inducing neuronal hyperexcitability of TG neurons and pain hypersensitivity in rats.
Learn More >In trials of monoclonal antibodies against calcitonin gene-related peptide or its receptor for prevention of episodic migraine, we observed two problematic aspects: a) The graphic presentations; b) the methods of calculating "response rates" (≥50% decrease of monthly migraine days from baseline).
Learn More >There are growing interests to study the molecular and cellular interactions among immune cells and sensory neurons in the dorsal root ganglia after peripheral nerve injury. Peripheral monocytic cells, including macrophages, are known to respond to a tissue injury through phagocytosis, antigen presentation, and cytokine release. Emerging evidence has implicated the contribution of dorsal root ganglia macrophages to neuropathic pain development and axonal repair in the context of nerve injury. Rapidly phenotyping (or "rapid isolation of") the response of dorsal root ganglia macrophages in the context of nerve injury is desired to identify the unknown neuroimmune factors. Here we demonstrate how our lab rapidly and effectively isolates macrophages from the dorsal root ganglia using an enzyme-free mechanical dissociation protocol. The samples are kept on ice throughout to limit cellular stress. This protocol is far less time consuming compared to the standard enzymatic protocol and has been routinely used for our Fluorescence-activated Cell Sorting analysis.
Learn More >Immune-nociceptor connections are found in animals across phyla. Local inflammation and/or damage results in increased nociceptive sensitivity of the affected area. However, in mammals, immune responses far from peripheral nociceptors, such as immune responses in the gut, produce a general increase in peripheral nociceptive sensitivity. This phenomenon has not, to our knowledge, been found in other animal groups. We found that consuming heat-killed pathogens reduced the tactile force needed to induce a defensive strike in the caterpillar . This increase in the nociceptive sensitivity of the body wall is probably part of the reconfiguration of behaviour and physiology that occurs during an immune response (e.g. sickness behaviour). This increase may help enhance anti-predator behaviour as molecular resources are shifted towards the immune system. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Chemically induced nociception has not yet been studied intensively in genetically tractable models. Hence, our goal was to establish a assay that can be used to study the cellular and molecular/genetic bases of chemically induced nociception. larvae exposed to increasing concentrations of hydrochloric acid (HCl) produced an increasingly intense aversive rolling response. HCl (0.5%) was subthreshold and provoked no response. All classes of peripheral multidendritic (md) sensory neurons (classes I-IV) are required for full responsiveness to acid, with class IV making the largest contribution. At the cellular level, classes IV, III and I showed increases in calcium following acid exposure. In the central nervous system, Basin-4 second-order neurons are the key regulators of chemically induced nociception, with a slight contribution from other types. Finally, chemical nociception can be sensitized by tissue damage. Subthreshold HCl provoked chemical allodynia in larvae 4 h after physical puncture wounding. Pinch wounding and UV irradiation, which do not compromise the cuticle, did not cause chemical allodynia. In sum, we developed a novel assay to study chemically induced nociception in larvae. This assay, combined with the high genetic resolving power of should improve our basic understanding of fundamental mechanisms of chemical nociception. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >This analysis assessed migraine-related burden and treatment decisions in Chronic Migraine Epidemiology and Outcomes (CaMEO) Study survey respondents who stopped taking acute prescription medications for migraine.
Learn More >To explore predictors of dropout of patients with chronic musculoskeletal pain from an interdisciplinary chronic pain management programme, and to develop and validate a multivariable prediction model, based on the Extended Common-Sense Model of Self-Regulation (E-CSM).
Learn More >Animals have quick-acting nociceptive reflexes that protect them from tissue damage. Some taxa have also evolved the capacity for pain. Pain appears to be linked to long-term changes in motivation brought about by the aversive nature of the experience. Pain presumably enhances long-term protection through behaviour modification based, in part, on memory. However, crustaceans have long been viewed as responding purely by reflex and thus not experiencing pain. This paper considers behavioural and physiological criteria that distinguish nociception from potential pain in this taxon. These include trade-offs with other motivational systems and prolonged motivational change. Complex, prolonged grooming or rubbing demonstrate the perception of the specific site of stimulus application. Recent evidence of fitness-enhancing, anxiety-like states is also consistent with the idea of pain. Physiological changes in response to noxious stimuli mediate some of the behavioural change. Rapid avoidance learning and prolonged memory indicate central processing rather than mere reflexes. Thus, available data go beyond the idea of just nociception. However, the impossibility of total proof of pain described in ways appropriate for our own species means that pain in crustaceans is still disputed. Pain in animals should be defined in ways that do not depend on human pain experience. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Placebo hypoalgesia provides pain relief for individuals via the expectation of a beneficial or therapeutic outcome, while nocebo hyperalgesia results in increased pain in response to anxious anticipation of harmful outcomes. These forms of placebo pain modulation can be induced through repeated associations, verbal cues, and social interactions. Understanding these methods of pain modulation can provide greater insight into the psychosocial contexts of pain modulation, as well as develop novel approaches to pain management.
Learn More >Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine. This trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing to healthy participants.
Learn More >Adult atopic dermatitis (AD) patients report skin pain, but the relationship with disease severity, anatomical location, and use of pain medication is unclear.
Learn More >Chronic primary pain (CPP) is one of seven diagnostic groups within the proposed classification of chronic pain in ICD-11. Our aims were to apply the proposed ICD-11 criteria in a large cohort of chronic pain patients participating in the Chronic Pain Self-Management Program (CPSMP) and further investigate whether participants with CPP differed from participants with chronic secondary pain (CSP) regarding health, health expenditure, and the effect of participating in the CPSMP.
Learn More >Chronic pain is increasingly recognized as a common and disabling problem for people living with HIV (PLWH). In a recent systematic review of psychosocial factors associated with chronic pain in PLWH, it was reported that very few studies to date have examined protective psychological factors that might help mitigate chronic pain for PLWH. The current study examined pain-specific resilience in relation to clinical and experimental pain, as well as pain coping in PLWH and chronic pain. Pain-specific resilience specifically refers to the ability to maintain relatively stable, healthy levels of psychological and physical functioning in the face of ongoing and persistent pain.
Learn More >Chemotherapy-induced neuropathic pain (CINP) is one of the most severe side effects of anticancer agents, such as platinum- and taxanes-derived drugs (oxaliplatin, cisplatin, carboplatin and paclitaxel). CINP may even be a factor of interruption of treatment and consequently increasing the risk of death. Besides that, it is important to take into consideration that the incidence of cancer is increasing worldwide, including colorectal, gastric, lung, cervical, ovary and breast cancers, all treated with the aforementioned drugs, justifying the concern of the medical community about the patient's quality of life. Several physiopathological mechanisms have already been described for CINP, such as changes in axonal transport, mitochondrial damage, increased ion channel activity and inflammation in the central nervous system (CNS). Another less frequent event that may occur after chemotherapy, particularly under oxaliplatin treatment, is the central neurotoxicity leading to disorders such as mental confusion, catatonia, hyporeflexia, etc. To date, no pharmacological therapy has shown satisfactory effect in these cases. In this scenario, duloxetine is the only drug currently in clinical use. Peroxisome proliferator-activated receptors (PPARs) belong to the class of nuclear receptors and are present in several tissues, mainly participating in lipid and glucose metabolism and inflammatory response. There are three PPAR isoforms: α, β/δ and γ. PPARγ, the protagonist of this review, is expressed in adipose tissue, large intestine, spleen and neutrophils. This subtype also plays important role in energy balance, lipid biosynthesis and adipogenesis. The effects of PPARγ agonists, known for their positive activity on type II diabetes mellitus, have been explored and present promising effects in the control of neuropathic pain, including CINP, and also cancer. This review focuses largely on the mechanisms involved in chemotherapy-induced neuropathy and the effects of the activation of PPARγ to treat CINP. It is the aim of this review to help understanding and developing novel CINP therapeutic strategies integrating PPARγ signalling.
Learn More >Pain hypersensitivity has been described as one of the most disabling symptoms of fibromyalgia syndrome (FMS). Here we analyzed the relationship between an anti-inflammatory diet profile and the pressure pain thresholds (PPTs) of tender point sites and other fibromyalgia-related symptoms in patients with FMS.
Learn More >Children with migraine headaches appear to have a range of sleep disturbances. The aim of the present study was to assess the NREM sleep instability in a population of school-aged individuals affected by migraine without aura (MoA). Thirty-three children with MoA (20 males, 13 females, mean age 10.45 ± 2.06 years) underwent to overnight Polysomnographic (PSG) recordings and Cyclic Alternating Pattern (CAP) analyses accordingly with international criteria. MoA group showed a reduction in sleep duration parameters (TIB, SPT, TST; ≤ 0.001 for all) and in arousal index during REM sleep and an increase in awakenings per hour (AWK/h) vs. Controls (C) ( = 0.008). In particular, MoA children showed a reduced CAP rate% ( ≤ 0.001), CAP rate% in S1 ( ≤ 0.001) and CAP rate% in SWS ( = 0.004) vs. C. Moreover, A phases distribution were characterized by a reduction in slow wave components (total number CAP A1%, CAP A1 index) ( ≤ 0.001) and an increase of fast components representation (total number of CAP A2% and CAP A3%) ( < 0.001) in MoA vs. C. Moreover, MoA children showed an increased A1 and A2 mean duration ( ≤ 0.001). Our findings show a reduction of arousability in MoA group and lower NREM lower sleep instability associated with MoA in children.
Learn More >The exacerbation of a clinical condition or the occurrence of negative symptoms after an inert substance dispensation or a sham treatment is known as "nocebo effect." Nocebo is the psychobiological effect due to the negative psychosocial context that accompanies a therapy, and it is a direct consequence of negative expectations by the patients and their own personal characteristics. Although the clinical relevance of the phenomenon is now recognized, a small number of studies have tried to ascertain its neural underpinnings (that it means nocebo responses). Moreover, there is no consensus on the brain networks involved in nocebo processes in humans. In particular, nocebo hyperalgesia has attracted almost no research attention. We conducted a mini-review on the few experimental pain functional magnetic resonance imaging (fMRI) studies of nocebo responses to discuss how negative expectancies and conditioning effects engage brain networks to modulate pain experiences. Moreover, we present possible clinical implications considering Alzheimer's disease and behavioral frontotemporal dementia, in which the existence of a hypothetically disrupted neurocognitive anticipatory network-secondary to an endogenous pain modulatory system damage-may be responsible for pain processing alterations.
Learn More >A significant body of experimental evidence has demonstrated that it is possible to induce the illusion of ownership of a fake limb or even an entire fake body using multisensory correlations. Recently, immersive virtual reality has allowed users to experience the same sensations of ownership over a virtual body inside an immersive virtual environment, which in turn allows virtual reality users to have the feeling of being "embodied" in a virtual body. Using such virtual embodiment to manipulate body perception is starting to be extensively investigated and may have clinical implications for conditions that involve altered body image such as chronic pain. Here, we review experimental and clinical studies that have explored the manipulation of an embodied virtual body in immersive virtual reality for both experimental and clinical pain relief. We discuss the current state of the art, as well as the challenges faced by, and ideas for, future research. Finally, we explore the potentialities of using an embodied virtual body in immersive virtual reality in the field of neurorehabilitation, specifically in the field of pain.
Learn More >The negative side effects of opioid-based narcotics underscore the search for alternative non-opioid bioactive compounds that act on the peripheral nervous system to avoid central nervous system-mediated side effects. The transient receptor potential V1 ion channel (TRPV1) is a peripheral pain generator activated and sensitized by heat, capsaicin, and a variety of endogenous ligands. TRPV1 contributes to peripheral sensitization and hyperalgesia, in part, triggering the release of proinflammatory peptides, such as calcitonin gene-related peptide (CGRP), both locally and at the dorsal horn of the spinal cord. Ultrapotent exogenous TRPV1 agonists, such as resiniferatoxin identified in the latex of the exotic , trigger hyperalgesia followed by long lasting, peripheral analgesia. The present study reports on the analgesic properties of , a relative of , native to the Southern United States. The study hypothesized that latex extract induces long-lasting, non-opioid peripheral analgesia in a rat model of inflammatory pain. Both inflamed and non-inflamed adult male and female rats were injected with the methanolic extract of latex into the hindpaw and changes in pain behaviors were reassessed at various time points up to 4 weeks. Primary sensory neuron cultures also were treated with the latex extract or vehicle for 15 min followed by stimulation with the TRPV1 agonist capsaicin. Results showed that latex extract evoked significant pain behaviors in both male and female rats at 20 min post-injection and lasting around 1-2 h. At 6 h post-injection, analgesia was observed in male rats that lasted up to 4 weeks, whereas in females the onset of analgesia was delayed to 72 h post-injection. In sensory neurons, latex extract significantly reduced capsaicin-evoked CGRP release. Blocking TRPV1, but not opioid receptors, attenuated the onset of analgesia and capsaicin-induced CGRP release. Latex was analyzed by mass spectrometry and eleven candidate compounds were identified and reported here. These findings indicate that phytochemicals in the latex induce hyperalgesia followed by peripheral, non-opioid analgesia in both male and female rats, which occurs in part TRPV1 and may provide novel, non-opioid peripheral analgesics that warrant further examination.
Learn More >Migraine is a common headache disorder characterized by unilateral, intense headaches. In migraine with aura, the painful headache is preceded by focal neurological symptoms that can be visual, sensory, or motor in nature. Spreading depression (the most likely cause of migraine with aura and perhaps related headache pain) results in increased neuronal excitability and related increases in inflammation and production of reactive oxygen species. This in turn can promote the transformation of low-frequency, episodic migraine into higher-frequency and eventually chronic migraine. Though migraine affects 11% of adults worldwide, with 3% experiencing chronic headache, existing therapies offer only modest benefits. Here, we focus on the mechanisms by which environmental enrichment (i.e., volitionally increased intellectual, social, and physical activity) mitigates spreading depression. In prior work, we have shown that exposure to environmental enrichment reduces susceptibility to spreading depression in rats. This protective effect is at least in part due to environmental enrichment-mediated changes in the character of serum exosomes produced by circulating immune cells. We went on to show that environmental enrichment-mimetic exosomes can be produced by stimulating dendritic cells with low levels of interferon gamma (a cytokine that is phasically increased during environmental enrichment). Interferon gamma-stimulated dendritic cell exosomes (IFNγ-DC-Exos) significantly improve myelination and reduce oxidative stress when applied to hippocampal slice cultures. Here, we propose that they may also be effective against spreading depression. We found that administration of IFNγ-DC-Exos reduced susceptibility to spreading depression and , suggesting that IFNγ-DC-Exos may be a potential therapeutic for migraine.
Learn More >Opioid analgesics have been used for thousands of years in the treatment of pain and related disorders, and have become among the most widely prescribed medications. Among opioid analgesics, mu opioid receptor (MOR) agonists are the most commonly used and are indicated for acute and chronic pain management. However, their use results in a plethora of well-described side-effects. From selective delta opioid receptor (DOR) and kappa opioid receptor (KOR) agonists to multitarget MOR/DOR and MOR/KOR ligands, medicinal chemistry provided different approaches aimed at the development of opioid analgesics with an improved pharmacological and tolerability fingerprint. The emergent medicinal chemistry strategy to develop ameliorated opioid analgesics is based upon the concept that functional selectivity for G-protein signalling is necessary for the therapeutic effect, whether β-arrestin recruitment is mainly responsible for the manifestation of side effects, including the development of tolerance after repeated administrations. This review summarises most relevant biased MOR, DOR, KOR and multitarget MOR/DOR ligands synthesised in the last decade and their pharmacological profile in "in vitro" and "in vivo" studies. Such biased ligands could have a significant impact on modern drug discovery and represent a new strategy for the development of better-tolerated drug candidates.
Learn More >The aim of this study was to compare the effectiveness of a combined intervention of manual therapy and exercise (MET) versus usual care (UC), on disability, pain intensity and global perceived recovery, in patients with non-specific chronic neck pain (CNP).
Learn More >Both temporomandibular disorders myalgia (TMDM) and fibromyalgia (FM) have been linked to central and peripheral changes in serotonin availability. The precursor of serotonin, tryptophan (TRP), is mainly catabolized via another pathway to produce kynurenine (KYN), but whether changes of this pathway are present in TMDM and FM are still unclear.
Learn More >The relationship between gut microbiota and neurological diseases, including chronic pain, has received increasing attention. The gut microbiome is a crucial modulator of visceral pain, whereas recent evidence suggests that gut microbiota may also play a critical role in many other types of chronic pain, including inflammatory pain, headache, neuropathic pain, and opioid tolerance. We present a narrative review of the current understanding on the role of gut microbiota in pain regulation and discuss the possibility of targeting gut microbiota for the management of chronic pain. Numerous signalling molecules derived from gut microbiota, such as by-products of microbiota, metabolites, neurotransmitters, and neuromodulators, act on their receptors and remarkably regulate the peripheral and central sensitisation, which in turn mediate the development of chronic pain. Gut microbiota-derived mediators serve as critical modulators for the induction of peripheral sensitisation, directly or indirectly regulating the excitability of primary nociceptive neurones. In the central nervous system, gut microbiota-derived mediators may regulate neuroinflammation, which involves the activation of cells in the blood-brain barrier, microglia, and infiltrating immune cells, to modulate induction and maintenance of central sensitisation. Thus, we propose that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain.
Learn More >The pathophysiology of fibromyalgia includes central and peripheral factors. Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, are involved in peripheral and central nervous system development of pain and hyperalgesia. Few studies have examined circulating nerve growth factor and brain-derived neurotrophic factor in fibromyalgia or have investigated whether exercise interventions affect the levels of these peptides.
Learn More >: Calcitonin Gene-Related Peptide (CGRP) plays a crucial role in migraine pathophysiology. A novel specific treatment strategy for the prevention of migraine incorporates monoclonal antibodies (mAbs) against CGRP and its canonical receptor. Eptinezumab, fremanezumab and galcanezumab block CGRP mediated effects by binding to the peptide, while erenumab blocks the CGRP receptor. : Following a brief overview of pharmacological characteristics, we will review phase III trials for the use of CGRP mAbs in the prevention of episodic and chronic migraine. : All four CGRP mAbs demonstrated an excellent safety, tolerability and efficacy profile in migraine patients. Across all trials mAbs showed superior efficacy for the reduction of monthly migraine days compared to placebo with a net benefit of 2.8 days. Neither cardiovascular nor immunological safety concerns have emerged from clinical trials. Fremanezumab, galcanezumab, and erenumab are approved in the USA and Europe. Based on trial data there is no reason why these mAbs should not become first line therapies in future. For now, we advocate for the use of mAbs in migraine prevention for patients who failed a minimum of two standard oral treatments based on the novelty and costs of this approach. mAbs are also effective in patients with medication overuse and with comorbid depression or anxiety disorders. Taken together, mAbs are likely to usher in a new era in migraine prevention and provide significant value to patients.
Learn More >The role of state anxiety and state fear in placebo effects is still to be determined. We aimed to investigate the effect of fear of movement-related pain (FMRP) and contextual pain related anxiety (CPRA) on the magnitude of placebo analgesia induced by verbal suggestion. Fifty-six female participants completed a modified voluntary joystick movement paradigm (VJMP) where half participated in a predictable pain condition (PC), in which one of the joystick movements is always followed by pain and the other movement is never followed by pain, and half in an unpredictable pain condition (UC), in which pain was delivered unpredictably. By varying the level of pain predictability, FMRP and CPRA were induced in PC and UC respectively. Colour stimuli were presented at the beginning of each trail. Half of the participants were verbally informed that the green or red colour indicated less painful stimuli (experimental groups), the other half did not receive any suggestion (control groups). We measured self-reported pain intensity, expectancy of pain intensity (PC only), pain related fear and anxiety (eyeblink startle response and self-ratings) and avoidance behaviour (movement-onset latency and duration). The results indicate that the placebo effect was successfully induced in both experimental conditions. In the PC, the placebo effect was predicted by expectancy. Despite the fact that FMRP and CPRA were successfully induced, no difference was found in the magnitude of the placebo effect between PC and UC. Concluding, we did not find a divergent effect of fear and anxiety on placebo analgesia.
Learn More >The role of urea in neuronal degeneration and sensitization: an in vitro model of uremic neuropathy.
Background Uremic neuropathy commonly affects patients with chronic kidney disease (CKD), with painful sensations in the feet, followed by numbness and weakness in the legs and hands. The symptoms usually resolve following kidney transplantation, but the mechanisms of uremic neuropathy and associated pain symptoms remain unknown. As blood urea levels are elevated in patients with CKD, we examined the morphological and functional effects of clinically observed levels of urea on sensory neurons. Methods Rat DRG neurons were treated with 10 or 50 mMol/L urea for 48 hours, fixed and immunostained for PGP9.5 and βIII tubulin immunofluorescence, ,. Neurons were also immunostained for TRPV1, TRPM8 and Gap43 expression, and the capsaicin sensitivity of urea or vehicle treated neurons was determined. Results Urea treated neurons had degenerating neurites with diminished PGP9.5 immunofluorescence, and swollen, retracted growth cones. βIII tubulinappeared clumped after urea treatment. Neurite lengths were significantly reduced to 60 ± 2.6 % (10 mMol/L, **P<0.01), and to 56.2 ± 3.3 %, (50 mMol/L, **P<0.01), urea treatment for 48 hours, compared with control neurons. Fewer neurons survived urea treatment, with 70.08 ± 13.3% remaining after10 mMol/L (*P<0.05), and 61.49 ± 7.4 % after 50 mMol/L urea treatment (**P<0.01), compared with controls. The proportion of neurons expressing TRPV1 was reduced after urea treatment, but not TRPM8 expressing neurons. In functional studies, treatment with urea resulted in dose-dependent neuronal sensitization. Capsaicin responses were significantly increased to 115.29 ± 3.4 % (10 mMol/L, **P<0.01) and 125.3 ± 4.2% (50 mMol/L, **P<0.01), compared with controls. Sensitization due to urea was eliminated in the presence of the TRPV1 inhibitor SB705498, the MEK inhibitor PD98059, the PI3 kinase inhibitor LY294002, and the TRPM8 inhibitor AMTB. Conclusion Neurite degeneration and sensitization are consistent with uremic neuropathy, , and provide a disease-relevant model to test new treatments.
Learn More >Current theories associated with the cause of tension type headache are mostly focused on muscle tissues. No study has investigated the presence of role of nerve tissues in this population.
Learn More >Intervertebral disc herniation is one of the common causes of low back pain. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator drugs have been shown to reduce pain in several animal models. The present study examines if early treatment with the drug metformin, an indirect AMPK activator, and/or O304, a new direct AMPK activator, can reduce the mechanical hypersensitivity that develops after lumbar disc puncture in mice.
Learn More >Chronic pruritus causes major morbidity in epidermolysis bullosa (EB). The substance P-neurokinin 1 receptor (SP-NK1) pathway is a promising target for treating EB-related pruritus.
Learn More >Emerging from the depths of evolution, pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors (i.e., PAC1, VPAC1, VPAC2) are present in multicellular organisms from Tunicates to humans and govern a remarkable number of physiological processes. Consequently, the clinical relevance of PACAP systems spans a multifaceted palette that includes more than 40 disorders. We aimed to present the versatility of PACAP1-38 actions with a focus on three aspects: (1) when PACAP1-38 could be a cause of a malfunction, (2) when PACAP1-38 could be the cure for a malfunction, and (3) when PACAP1-38 could either improve or impair biology. PACAP1-38 is implicated in the pathophysiology of migraine and post-traumatic stress disorder whereas an outstanding protective potential has been established in ischemia and in Alzheimer's disease. Lastly, PACAP receptors could mediate opposing effects both in cancers and in inflammation. In the light of the above, the duration and concentrations of PACAP agents must be carefully set at any application to avoid unwanted consequences. An enormous amount of data accumulated since its discovery (1989) and the first clinical trials are dated in 2017. Thus in the field of PACAP research: "this is not the end, not even the beginning of the end, but maybe the end of the beginning."
Learn More >Remifentanil is commonly used clinically for perioperative pain relief, but it may induce postoperative hyperalgesia. Low doses of ketamine have remained a common choice in clinical practice, but the mechanisms of ketamine have not yet been fully elucidated. In this study, we examined the possible effects of ketamine on calcium/calmodulin-dependent protein kinase II α (CaMKIIα) and N-methyl-d-aspartate receptor (NMDAR) subunit NR2B in a mouse model of remifentanil-induced postoperative hyperalgesia (RIPH) in the primary somatosensory cerebral cortex (SI) region. The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were used to assess mechanical allodynia and thermal hyperalgesia, respectively, before and after intraoperative remifentanil administration. Before surgery, mice received intrathecal injections of the following drugs: ketamine, NMDA, BayK8644 (CaMKII activator), and KN93 (CaMKII inhibitor). Immunofluorescence was performed to determine the anatomical location and expression of activated CaMKIIα, phosphorylated CaMKIIα (p-CaMKIIα). Additionally, western blotting was performed to assess p-CaMKIIα and NMDAR expression levels in the SI region. Remifentanil decreased the PWMT and PWTL at 0.5 h, 2 h, and 5 h and increased p-CaMKIIα expression in the SI region. Ketamine increased the PWMT and PWTL and reversed the p-CaMKIIα upregulation. Both BayK8644 and NMDA reversed the effect of ketamine, decreased the PWMT and PWTL, and upregulated p-CaMKIIα expression. In contrast, KN93 enhanced the effect of ketamine by reducing hyperalgesia and downregulating p-CaMKIIα expression. These results suggested that ketamine reversed RIPH by inhibiting the phosphorylation of CaMKIIα and the NMDA receptor in the SI region in mice.
Learn More >We investigated the efficacy of duloxetine on hyperalgesia, histopathological and radiographic findings, pain-related sensory innervation of dorsal-root ganglia (DRG), and spinal changes in a rat model of induced hip osteoarthritis (OA). The right hip joints of male Sprague-Dawley rats (n = 6 rats/group) in the Sham group were injected with 25 μL of sterile saline and 25 μL of sterile saline with 2 mg of monosodium iodoacetate (MIA) were injected to the MIA + Vehicle and MIA + Duloxetine groups. We injected duloxetine 20 mg/kg intraperitoneally in the MIA + Duloxetine group 28 days after injection, whereas rats in the MIA + Vehicle group were injected with 0.5 mL of 20% dimethyl sulfoxide. We assessed hyperalgesia, histopathological changes, immunoreactive (-ir) neurons for calcitonin gene-related peptide and activating transcription factor 3 in DRG, and immunoreactive neurons for ionized-calcium-binding adaptor molecule 1 (Iba1) in the dorsal horn of the spinal cord. MIA administration into the hip joint let to mechanical hyperalgesia of the ipsilateral hind paw (p < 0.05). A single injection of duloxetine significantly attenuated it in induced hip OA (p < 0.05) and suppressed the number of Iba1-ir microglia of the ipsilateral dorsal horn (p < 0.05). These results suggest that a single injection of duloxetine suppressed mechanical hyperalgesia and may influence the expression of Iba1 in the microglia of the ipsilateral dorsal horn in the MIA-induced hip OA. This finding implies the inhibitory effects of duloxetine against neuropathic pain, which may lead to a change of microglial activities. This article is protected by copyright. All rights reserved.
Learn More >In literature, osmophobia is reported as a specific migrainous symptom with a prevalence of up to 95%. Despite the International Classification of Headache Disorders 2nd edition proposal of including osmophobia among accompanying symptoms, it was no longer mentioned in the ICHD 3rd edition.
Learn More >Background and aims Aside from the long term side effects of a nerve injury in the upper extremity with devastating consequences there is often the problem of chronic neuropathic pain. The studies concerning the prevalence of persistent pain of neuropathic origin after peripheral nerve injuries are sparse. The prevalence and risk factors associated with chronic neuropathic pain after nerve injuries in the upper extremity were assessed. Methods A standardized data collection template was employed prospectively and retrospectively for all patients with traumatic nerve injuries accepted at the Hand Surgery Department, Uppsala, Sweden between 2010 and 2018. The template included demographic data, pain diagnosis, type of injured nerve, level of injury, date of the lesion and repair, type of procedure, reoperation, time since the procedure, S-LANSS questionnaire (Self report-Leeds Assessment of Neuropathic Symptoms and Signs), RAND-36 (Item short form health survey), QuickDASH (Disability of Shoulder, Arm and Hand) and additional questionnaires concerned medication, pain intensity were sent to 1,051 patients with nerve injuries. Partial proportional odds models were used to investigate the association between persistent pain and potential predictors. Results More than half of the patients undergoing a surgical procedure developed persistent pain. Prevalence of neuropathic pain was 73% of the patients with pain (S-LANSS ≥ 12 or more). Multivariate analysis indicated that injury of a major nerve OR 1.6 (p = 0.013), years from surgery OR 0.91 (p = 0.01), younger age OR 0.7 (p < 0.001), were the main factors for predicting pain after surgery. The type of the nerve injured was the strongest predictor for chronic pain with major nerves associated with more pain (p = 0.019). Conclusions A high prevalence of chronic pain and neuropathic pain with a negative impact on quality of life and disability were found in patients after traumatic nerve injury. Major nerve injury, younger age and less time from surgery were predictors for chronic pain.
Learn More >This study aims to compare the management practices of a headache specialist with non-headache specialists in the treatment of children with migraine. The use of appropriate rescue medications and prophylactic agents, application of neuroimaging, and short-term outcomes are compared in children treated by the two groups of physicians.
Learn More >Patients with migraine frequently report ocular or visual symptoms including aura, photophobia, and eye pain. Using validated instruments, our group previously reported that due to these symptoms, patients have marked reductions in visual quality of life. In chronic migraine, these reductions can be as substantial as those reported for other neuro-ophthalmic diseases such as multiple sclerosis with optic neuritis and idiopathic intracranial hypertension. Because the instruments take several different dimensions into account, we were unable to determine which ocular symptom(s) contributed to reduced visual quality of life. The purpose of this investigation was to attempt to determine which ocular symptom(s) were driving the observed reduction in visual quality of life.
Learn More >Migraine is a neurovascular disease with recurrent headache attacks. A polymorphism (rs2651899) of the PRDM16 gene, which is associated with migraine, was identified in recent genome-wide association studies. The potential role of the PRDM16 rs2651899 polymorphism in migraine is still unknown. Therefore, we conducted this systematic review and meta-analysis to examine this issue.
Learn More >Despite the heightened urgency of the current prescription opioid crisis, few psychotherapies have been evaluated for chronic pain patients receiving long-term opioid analgesics. Current psychological pain treatments focus primarily on ameliorating negative affective processes, yet basic science suggests that risk for opioid misuse is linked with a dearth of positive affect. Interventions that modulate positive psychological processes may produce therapeutic benefits among patients with opioid-treated chronic pain. The aim of this study was to conduct a theory-driven mechanistic analysis of proximal outcome data from a Stage 2 randomized controlled trial of Mindfulness-Oriented Recovery Enhancement (MORE), an integrative intervention designed to promote positive psychological health.
Learn More >Prescribed opioids for chronic pain management contribute significantly to the opioid crisis. There is a need to understand the real-world benefits that, despite risks, lead chronic pain patients to persist in opioid use. Negative reinforcement models of addiction posit that individuals use substances to reduce aversive states but have seldom been applied to prescribed opioids. Using ecological momentary assessment, we examined reciprocal associations between opioid use and physical pain, for which opioids are prescribed, and negative affect (NA), for which they are not.
Learn More >Singing can have a range of health benefits; this paper reviews evidence of the effects of group singing for chronic pain in people with long-term health conditions.
Learn More >To evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of oral NKTR-181 (oxycodegol), a novel full mu-opioid receptor agonist, relative to oral oxycodone.
Learn More >Among the various regulators of the nervous system, the gut microbiota has been recently described to have the potential to modulate neuronal cells activation. While bacteria-derived products can induce aversive responses and influence pain perception, recent work suggests that "abnormal" microbiota is associated with neurological diseases such as Alzheimer's, Parkinson's disease or autism spectrum disorder (ASD). Here we review how the gut microbiota modulates afferent sensory neurons function and pain, highlighting the role of the microbiota/gut/brain axis in the control of behaviors and neurological diseases. We outline the changes in gut microbiota, known as dysbiosis, and their influence on painful gastrointestinal disorders. Furthermore, both direct host/microbiota interaction that implicates activation of "pain-sensing" neurons by metabolites, or indirect communication via immune activation is discussed. Finally, treatment options targeting the gut microbiota, including pre- or probiotics, will be proposed. Further studies on microbiota/nervous system interaction should lead to the identification of novel microbial ligands and host receptor-targeted drugs, which could ultimately improve chronic pain management and well-being.
Learn More >Pain (nociceptive) input caudal to a spinal contusion injury can undermine long-term recovery and increase tissue loss (secondary injury). Prior work suggests that nociceptive stimulation has this effect because it fosters the breakdown of the blood-spinal cord barrier (BSCB) at the site of injury, allowing blood to infiltrate the tissue. The present study examined whether these effects impact tissue rostral and caudal to the site of injury. In addition, the study evaluated whether cutting communication with the brain, by means of a rostral transection, affects the development of hemorrhage. Eighteen hours after rats received a lower thoracic (T11-12) contusion injury, half underwent a spinal transection at T2. Noxious electrical stimulation (shock) was applied 6 h later. Cellular assays showed that, in non-transected rats, nociceptive stimulation increased hemoglobin content, activated pro-inflammatory cytokines and engaged signals related to cell death at the site of injury. These effects were not observed in transected animals. In the next experiment, the spinal transection was performed at the time of contusion injury. Nociceptive stimulation was applied 24 h later and tissue was sectioned for microscopy. In non-transected rats, nociceptive stimulation increased the area of hemorrhage and this effect was blocked by spinal transection. These findings imply that the adverse effect of noxious stimulation depends upon spared ascending fibers and the activation of rostral (brain) systems. If true, stimulation should induce less hemorrhage after a severe contusion injury that blocks transmission to the brain. To test this, rats were given a mild, moderate, or severe, injury and electrical stimulation was applied 24 h later. Histological analyses of longitudinal sections showed that nociceptive stimulation triggered less hemorrhage after a severe contusion injury. The results suggest that brain-dependent processes drive pain-induced hemorrhage after spinal cord injury (SCI).
Learn More >Dysautonomia and headache are 2 common diagnoses within pediatric neurology; in the case of dysautonomia, a lack of consideration may lead to misdiagnosis. Despite being common conditions, there is a lot to learn about each individually as well as collectively. Many of the symptoms between headache and dysautonomia patients overlap making the diagnosis difficult. Migraine patients often exhibit symptoms of dysautonomia, namely postural orthostatic tachycardia syndrome (POTS); yet these symptoms are overlooked or lumped in as a part of their migraine diagnosis. The distinction or coexistence between dysautonomia and headache is identified through a thorough history, a full exam, and an open mind. This is crucial for the treatment and outcomes of these patients. Struggles arise when critical treatment differences are overlooked because dysautonomia is not considered. In this review, we will look at the epidemiology of dysautonomia and headache with focus on POTS and migraine. We will then compare the clinical features of both conditions as well as some hypothesized pathophysiology overlaps. We will conclude by summarizing the diagnostic approach and multitiered treatment options for POTS and migraine.
Learn More >Injury occurring in the neonatal period in mammals is known to induce plasticity in pain pathways that may lead to pain dysfunction in later life. Whether these effects are unique to the mammalian nervous system is not well understood. Here, we investigate whether similar effects of early-life injury are found in a large-brained comparative model, the cephalopod . We show that the peripheral nervous system of undergoes profound and permanent plasticity after injury of peripheral tissue in the early post-hatching period, but not after the same injury given in the later juvenile period. Additionally, both innate defensive behaviour and learning are impaired by injury in early life. We suggest that these similar patterns of nervous system and behavioural remodelling that occur in squid and in mammals indicate an adaptive value for long-lasting plasticity arising from early-life injury, and suggest that injuries inflicted in very early life may signal to the nervous system that the environment is highly dangerous. Thus, neonatal pain plasticity may be a conserved pattern whose purpose is to set the developing nervous system's baseline responsiveness to threat. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
Learn More >Although recent studies have shown that botulinum toxin-A (BTX-A) has a good analgesic effect on trigeminal neuralgia (TN) and peripheral neuropathic pain (PNP), the quality of evidence is low due to limited data. This meta-analysis is used to synthesize existing evidence for the treatment of these conditions with BTX-A.
Learn More >Patients with advanced cancer face a life-limiting condition that brings a high symptom burden that often includes pain, fatigue, and psychological distress. Psychosocial interventions have promise for managing symptoms, but need additional tailoring for these patients' specific needs. Patients with advanced cancer in the community also face persistent barriers – availability of interventions in community clinics, financial and illness-related factors – to accessing psychosocial interventions.
Learn More >Diminished pressure pain thresholds (PPTs) have been found in patients with cluster headache (CH), suggesting the presence of central sensitization. However, it is not known whether sensitization persists over time during the asymptomatic periods.
Learn More >Background and aims Persistent tendinopathies were previously considered solely as peripheral conditions affecting the local tendinous tissue until quantitative sensory testing identified involvement of altered pain processing. In similar fashion, pain in patients with persistent plantar fasciopathy may also involve more than local tissue. The aim of this pilot study was to investigate potential differences in conditioned pain modulation and pressure and thermal pain thresholds, between individuals with PF and healthy pain-free controls, as a precursor to a larger-scale study. Methods We assessed 16 individuals with plantar fasciopathy and 11 pain-free controls. Plantar fasciopathy diagnosis was: palpation pain of the medial calcaneal tubercle or the proximal plantar fascia, duration ≥3 months, pain intensity ≥2/10, and ultrasound-measured plantar fascia thickness ≥4 mm. Quantitative sensory tests were performed locally at the plantar heel and remotely on the ipsilateral elbow. Assessments included pain thresholds for pressure, heat and cold, and conditioned pain modulation measured as change in local resting pressure pain threshold with cold water hand immersion. Participants rated pain intensity at pain threshold. Additionally, the area and distribution of plantar fasciopathy pain was drawn on a digital body chart of the lower limbs. Descriptive analyses were performed and between-group differences/effects expressed as standardised mean differences (d). Results There was no conditioned pain modulation difference between participants with plantar fasciopathy and controls (d = 0.1). Largest effects were on local pressure pain threshold and reported pain intensity on pressure pain threshold (d > 1.8) followed by pain intensity for heat and cold pain thresholds (d = 0.3-1.5). According to the digital body chart, pain area extended beyond the plantar heel. Conclusions The unlikelihood of a difference in conditioned pain modulation yet a pain area extending beyond the plantar heel provide a basis for exploring altered pain processing in a larger-scale study. Implications This was the first study to investigate the presence of altered pain processing in individuals with plantar fasciopathy using a conditioned pain modulation paradigm and thermal pain thresholds. We found no indication of an altered pain processing based on these measures, however, patients rated pain higher on thresholds compared to controls which may be important to clinical practice and warrants further exploration in the future.
Learn More >Most of the clinical characteristics of cluster headache (CH) have been established through the observation of men with CH. Epidemiological data of CH in women are scarce especially in the Asian population. Here, we sought to assess the prevalence and clinical characteristics of women with CH in comparison to men in a prospective CH registry.
Learn More >This study evaluates the reporting quality of randomized controlled trials (RCTs) on acupuncture use for the treatment of postherpetic neuralgia and explores related factors.
Learn More >Animal studies have demonstrated anti-inflammatory, and anti-nociceptive properties of hyperbaric oxygen therapy (HBOT). However, physiological data are scarce in humans. In a recent experimental study, the authors used the burn injury (BI) model observing a decrease in secondary hyperalgesia areas (SHA) in the HBOT-group compared to a control-group. Surprisingly, a long-lasting neuroplasticity effect mitigating the BI-induced SHA-response was seen in the HBOT-preconditioned group. The objective of the present study, therefore, was to confirm our previous findings using an examiner-blinded, block-randomized, controlled, crossover study design.
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