Nociceptive Input Research Articles

Serotonin mediates stress-like effects on responses to non-nociceptive stimuli in the medicinal leech Hirudo verbana.

ABSTRACTNoxious stimuli can elicit stress in animals that produce a variety of adaptations including changes in responses to nociceptive and non-nociceptive sensory input. One example is stress-induced analgesia that may be mediated, in part, by the endocannabinoid system. However, endocannabinoids can also have pro-nociceptive effects. In this study, the effects of electroshock, one experimental approach for producing acute stress, were examined on responses to non-nociceptive mechanical stimuli and nociceptive thermal stimuli in the medicinal leech (Hirudo verbana). The electroshock stimuli did not alter the leeches’ responses to nociceptive stimuli, but did cause sensitization to non-nociceptive stimuli, characterized by a reduction in response threshold. These experiments were repeated with drugs that either blocked synthesis of the endocannabinoid transmitter 2-arachidonoylglycerol (2-AG) or transient receptor potential vanilloid (TRPV) channel, which is known to act as an endocannabinoid receptor. Surprisingly, neither treatment had any effect on responses following electroshock. However, the electroshock stimuli reliably increased serotonin (5-hydroxytryptamine or 5HT) levels in the H. verbana CNS. Injection of 5HT mimicked the effects of the electroshocks, sensitizing responses to non-nociceptive stimuli and having no effect on responses to nociceptive stimuli. Injections of the 5HT receptor antagonist methysergide reduced the sensitization effect to non-nociceptive stimuli after electroshock treatment. These results indicate that electroshocks enhance response to non-nociceptive stimuli but do not alter responses to nociceptive stimuli. Furthermore, while 5HT appears to play a critical role in this shock-induced sensitizing effect, the endocannabinoid system seems to have no effect.

Mindfulness Meditation Modulates Nociceptive-specific but Not Placebo-related Pain-predictive Patterns

Mindfulness meditation-induced pain relief is more effective and mechanistically distinct from placebo. Machine-learned multivariate patterns are highly specific and predictive of subjective pain responses. The Neurological Pain Signature (NPS) is a multivoxel pattern that is specific to direct nociceptive input. The Stimulus Intensity Independent Pain Signature-1 (SIIPS1) predicts pain beyond stimulus intensity and NPS response and explains placebo-related pain mechanisms, e.g., beliefs, conditioning. Because mindfulness meditation engages non-placebo mechanisms to reduce pain, we hypothesized that mindfulness-based analgesia would modulate the NPS but not SIIPS1. Forty healthy, pain-free individuals were randomly assigned to a four session (20 minutes/session) mindfulness (n=20) or book-listening control (n=20) regimen after baseline pain assessment. Following the respective interventions, BOLD scans were acquired during two heat series (ten, 12s stimuli of noxious 49°C) administered to the right calf at rest (pre-manipulation) followed by two heat series (post-manipulation) during mindfulness (meditation group) or rest (control group). Visual analog scale (VAS) pain ratings (0= "no pain"; 10="worst pain imaginable") were collected after each series. Stimulus-related activation beta maps were resampled to match the voxel dimensions of the NPS and SIIPS1 (canlab.github.io). Beta values were compared to respective signature weights by the dot product to create scalar response values to test study hypotheses. There was a significant pre vs. post X group interaction on NPS responses (p=.04, np2=.11). Post-hoc tests revealed that mindfulness meditation reduced NPS responses when compared to rest (p=.03, np2=.12) and the control group (p=.42, np2=.02). The ANOVA conducted on the SIIPS1 revealed no significant interactions (p=.33, np2=.02) or main effects of manipulation (p=.94, np2=.00) and group (p=.87, np2=.00). The present findings provide novel evidence that mindfulness directly modulates nociceptive-specific but not placebo-related neural mechanisms. Grant support from NCT03414138.

P 60 A fully human sensory neuron – keratinocyte co-culture model for investigating the neuro-cutaneous unit

Introduction: Traditionally, peripheral sensory neurons were seen as the sole transducers of external stimuli. However, the contribution of non-neuronal cells is increasingly recognized. In the epidermis, keratinocytes act as sensors and transmitters of somatosensory and nociceptive input. They form intimate connections with afferent intraepidermal nerve fibers at the neuro-cutaneous unit. A conserved mechanism of nerve fiber ensheathment was described up to human skin. Via release of signaling molecules like ATP, keratinocytes can activate nerve endings, induce action potentials, and thereby tune peripheral input. Material & Methods: We obtained primary human fibroblasts and keratinocytes from diagnostic skin punch biopsies. Induced pluripotent stem cell-derived sensory neurons were generated from fibroblasts. After four-week maturation, neurons were transferred into a two-comparted well chamber system and primary keratinocytes seeded in the opposite well. We tracked the formation of neurite-keratinocyte contacts via live-imaging and subsequently investigated these interactions by confocal and super-resolution fluorescence microscopy. Results: Upon barrier removal, neurites form the neuronal compartment actively grew towards keratinocytes and formed contacts within few days. Via discriminative labeling of keratinocyte and neuronal membranes, we identified several types of interactions. Neurites tunneled through keratinocyte cytoplasm and formed bouton-like structures in contact with keratinocytes. Furthermore, connexin 43, a hemichannel and gap junction forming pore protein expressed in keratinocytes, accumulated at neurite-keratinocyte contact sites. Discussion: We successfully established a fully human co-culture model of sensory neurons and keratinocytes maintaining viability over several days. Our 2D model reduces the multilayered complexity of native human skin, yet conserves ensheathment of sensory neurites as a feature of the NCU and showed Cx43 plaques as a potential signaling route for NCU communication. This approach inherits a high potential for translational investigations, bypassing challenges of heterologous animal co-culture models and facilitating the integration of patient derived neurons and keratinocytes.

CENTRAL PAIN MECHANISMS PREDICT PHYSICAL INACTIVITY AT 1-YEAR IN INDIVIDUALS WITH KNEE PAIN

Purpose: Pain is the primary clinical manifestation in individuals with osteoarthritis (OA). It is an unpleasant and distressing experience, particularly during weight-bearing activities, inhibiting activity, and reducing quality of life. Two groups of mechanisms cause OA pain: peripheral (local joint pain from joint pathology) and central (severely worsened pain due to brain and spinal cord processing of peripheral nociceptive inputs). Each contributes to varying extents at different times to an individual’s OA pain.

Epigenome-wide DNA methylation profiling of conditioned pain modulation in individuals with non-specific chronic low back pain

BackgroundThe pathoanatomic cause of chronic low back pain (cLBP) cannot be identified for up to 90% of individuals. However, dysfunctional processing of endogenous nociceptive input, measured as conditioned pain modulation (CPM), has been associated with cLBP and may involve changes in neuronal gene expression. Epigenetic-induced changes such as DNA methylation (DNAm) have been associated with cLBP.MethodsIn the present study, the relationship between CPM and DNAm changes in a sample of community-dwelling adults with nonspecific cLBP (n = 48) and pain-free controls (PFC; n = 50) was examined using reduced representation bisulfite sequencing. Gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify key pathways involved in efficient versus deficient CPM.ResultsBased on CPM efficiency, we identified 6006 and 18,305 differentially methylated CpG sites (DMCs) with q values < 0.01 among individuals with cLBP and PFCs, respectively. Most of the DMCs were hypomethylated and annotated to genes of relevance to pain, including OPRM1, ADRB2, CACNA2D3, GNA12, LPL, NAXD, and ASPHD1. In both cLBP and PFC groups, the DMCs annotated genes enriched many GO terms relevant to pain processing, including transcription regulation by RNA polymerase II, nervous system development, generation of neurons, neuron differentiation, and neurogenesis. Both groups also enriched the pathways involved in Rap1-signaling, cancer, and dopaminergic neurogenesis. However, MAPK-Ras signaling pathways were enriched in the cLBP, not the PFC group.ConclusionsThis is the first study to investigate the genome-scale DNA methylation profiles of CPM phenotype in adults with cLBP and PFCs. Based on CPM efficiency, fewer DMC enrichment pathways were unique to the cLBP than the PFCs group. Our results suggest that epigenetically induced modification of neuronal development/differentiation pathways may affect CPM efficiency, suggesting novel potential therapeutic targets for central sensitization. However, CPM efficiency and the experience of nonspecific cLBP may be independent. Further mechanistic studies are required to confirm the relationship between CPM, central sensitization, and nonspecific cLBP.

Anti-Nociceptive and Anti-Aversive Drugs Differentially Modulate Distinct Inputs to the Rat Lateral Parabrachial Nucleus

The lateral parabrachial nucleus (LPBN) plays an important role in the processing and establishment of pain aversion. It receives direct input from the superficial dorsal horn and forms reciprocal connections with the periaqueductal grey matter (PAG), which is critical for adaptive behaviour and the modulation of pain processing. Here, using in situ hybridization and optogenetics combined with in vitro electrophysiology, we characterized the spinal- and PAG-LPBN circuits of rats. We found spinoparabrachial projections to be strictly glutamatergic, while PAG neurons send glutamatergic and GABAergic projections to the LPBN. We next investigated the effects of drugs with anti-aversive and/or anti-nociceptive properties on these synapses: The µ-opioid receptor agonist DAMGO (10 µM) reduced spinal and PAG synaptic inputs onto LPBN neurons, and the excitability of LPBN neurons receiving these inputs. The benzodiazepine receptor agonist diazepam (5 µM) strongly enhanced GABAergic action at inhibitory PAG-LPBN synapses. The cannabinoid receptor agonist WIN 55,212-2 (5 µM) led to a reduction in inhibitory and excitatory PAG-LPBN synaptic transmission, without affecting excitatory spinoparabrachial synaptic transmission. Our study reveals that opioid, cannabinoid and benzodiazepine receptor agonists differentially affect distinct LPBN synapses. These findings may support the efforts to develop pinpointed therapies for pain patients. PerspectiveThe LPBN is an important brain region for the control of pain aversion versus recuperation, and as such constitutes a promising target for developing new strategies for pain management. We show that clinically-relevant drugs have complex and pathway-specific effects on LPBN processing of putative nociceptive and aversive inputs.

Photophobia in headache disorders: characteristics and potential mechanisms.

Photophobia is present in multiple types of headache disorders. The coexistence of photophobia and headache suggested the potential reciprocal interactions between visual and pain pathways. In this review, we summarized the photophobic characteristics in different types of headache disorders in the context of the three diagnostic categories of headache disorders: (1) primary headaches: migraine, tension-type headache, and trigeminal autonomic cephalalgias; (2) secondary headaches: headaches attributed to traumatic brain injury, meningitis, non-traumatic subarachnoid hemorrhage and disorder of the eyes; (3) painful cranial neuropathies: trigeminal neuralgia and painful optic neuritis. We then discussed potential mechanisms for the coexistence of photophobia and headache. In conclusion, the characteristics of photophobia are different among these headache disorders. The coexistence of photophobia and headache is associated with the interactions between visual and pain pathway at retina, midbrain, thalamus, hypothalamus and visual cortex. The communication between these pathways may depend on calcitonin gene-related peptide and pituitary cyclase-activating polypeptide transmission. Moreover, cortical spreading depression, an upstream trigger of headache, also plays an important role in photophobia by increased nociceptive input to the thalamus.

Presynaptic Interactions between Trigeminal and Cervical Nociceptive Afferents Supplying Upper Cervical Lamina I Neurons.

Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate for pain referral in primary headache syndromes. Lamina I neurons are central to this mechanism, as they relay convergent nociceptive input to supraspinal pain centers. Unfortunately, little is known about the interactions between trigeminal and cervical afferents supplying Lamina I neurons. Here, we used rats of both sexes to show that cervical and trigeminal afferents interact via presynaptic inhibition, where monosynaptic inputs to Lamina I neurons undergo unidirectional as well as reciprocal presynaptic control. This means that afferent-driven presynaptic inhibition shapes the way trigeminal and cervical Aδ-fiber and C-fiber input reaches Lamina I projection neurons (PNs) and local-circuit neurons (LCNs). We propose that this inhibition provides a feedforward control of excitatory drive to Lamina I neurons that regulates their convergent and cervical-specific or trigeminal-specific processing modes. As a consequence, disruption of the trigeminal and cervical afferent-driven presynaptic inhibition may contribute to development of primary headache syndromes.SIGNIFICANCE STATEMENT Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate for pain referral in primary headache syndromes. Lamina I neurons are central to this mechanism as they relay convergent nociceptive input to supraspinal pain centers. Here, we show that cervical and trigeminal afferents interact via presynaptic inhibition, where inputs to Lamina I neurons undergo unidirectional as well as reciprocal control. The afferent-driven presynaptic inhibition shapes the trigeminocervical Aδ-fiber and C-fiber input to Lamina I neurons. This inhibition provides control of excitatory drive to Lamina I neurons that regulates their convergent and cervical-specific or trigeminal-specific processing modes. Disruption of this control may contribute to development of primary headache syndromes.

Neural processes responsible for the translation of sustained nociceptive inputs into subjective pain experience.

Tracking and predicting the temporal structure of nociceptive inputs is crucial to promote survival, as proper and immediate reactions are necessary to avoid actual or potential bodily injury. Neural activities elicited by nociceptive stimuli with different temporal structures have been described, but the neural processes responsible for translating nociception into pain perception are not fully elucidated. To tap into this issue, we recorded electroencephalographic signals from 48 healthy participants receiving thermo-nociceptive stimuli with 3 different durations and 2 different intensities. We observed that pain perception and several brain responses are modulated by stimulus duration and intensity. Crucially, we identified 2 sustained brain responses that were related to the emergence of painful percepts: a low-frequency component (LFC, < 1Hz) originated from the insula and anterior cingulate cortex, and an alpha-band event-related desynchronization (α-ERD, 8-13Hz) generated from the sensorimotor cortex. These 2 sustained brain responses were highly coupled, with the α-oscillation amplitude that fluctuated with the LFC phase. Furthermore, the translation of stimulus duration into pain perception was serially mediated by α-ERD and LFC. The present study reveals how brain responses elicited by nociceptive stimulation reflect the complex processes occurring during the translation of nociceptive information into pain perception.

Neuroscientific evidence for pain being a classically conditioned response to trauma- and pain-related cues in humans.

Psychological trauma is typically accompanied by physical pain, and posttraumatic stress disorder (PTSD) often cooccurs with chronic pain. Clinical reports suggest that pain after trauma may be part of re-experiencing symptomatology. Classical conditioning can underlie visual re-experiencing because intrusions can occur as conditioned responses (CRs) to trauma-related cues. If individuals also experience pain to cues previously paired with, but not inflicting nociceptive stimulation anymore (ie, conditioned stimuli, CS), conditioning could also explain re-experiencing of pain. Sixty-five participants underwent classical conditioning, where painful electrocutaneous stimulation and aversive film clips served as unconditioned stimuli (US) in a 2 (pain/no pain) × 2 (aversive/neutral film) design. Conditioned stimuli were neutral pictures depicting contextual details from the films. One day later, participants were re-exposed to CS during a memory-triggering task (MTT). We assessed pain-CRs by self-report and an fMRI-based marker of nociceptive pain, the neurological pain signature (NPS), and recorded spontaneous daily-life pain intrusions with an e-diary. During conditioning, pain-signaling CS elicited more self-reported pain and NPS responses than no-pain-signaling CS. Possibly because the aversive film masked differences in participants' responses to pain-signaling CS vs no pain-signaling CS, pain-CRs during acquisition were most evident within the neutral film condition. When participants were re-exposed to CS during MTT, self-reported pain-CRs during the neutral film condition and, although more uncertain, NPS-CRs during the aversive film condition persisted. Of importance, participants with stronger pain-CRs showed a greater probability and severity of experiencing spontaneous pain intrusions during daily life. Our data support that spatiotemporally associating innocuous cues with pain (CS) endows these cues to elicit conditioned pain responses in the absence of noxious stimulation. In this way pain can emerge as a CR with emotional and sensory components. Classical conditioning presents a possible mechanism explaining pain intrusions and, more broadly, pain experienced without a nociceptive input.

Pleasant touch perception in borderline personality disorder and its relationship with disturbed body representation

BackgroundBorderline personality disorder (BPD) is characterized by altered perception of affective stimuli, including abnormal evaluation of nociceptive input. However, whether or not perceptual alterations are present for its positive counterpart, i.e. pleasant touch (PT), has not yet been examined.MethodsIn the present study, we applied standardized PT stimuli to the hands of 25 patients with BPD and 25 healthy controls (HC) and compared their perception. We used the affect-modulated acoustic startle response as a physiological correlate of affective processing. We further explored the effect of PT stimulation on dissociative experiences in BPD.ResultsCompared to HC, BPD perceived PT as less pleasant and less intense. The effect on perceived valence of touch was large even after controlling for the effect of reduced perceived intensity of touch (ƞ2 = .29). We further found qualitative alterations in touch perception in BPD, who rated the touch as significantly rougher and firmer compared to HC. There was a positive correlation between perceived valence of touch and changes in dissociative experiences in terms of body ownership of the stimulated body part from pre to post stimulation, suggesting that a more negative evaluation of touch is associated with an increase in body-related dissociative experiences, while a positive perception of touch might be related to a reduction of these dissociative experiences.ConclusionsOur results confirm BPD-associated disturbances in the processing of affective somatosensory stimuli and indicate that not only pain perception but also pleasant touch perception is diminished in BPD. We discuss the role of altered touch perception for BPD psychopathology and its potential role for new treatment approaches.

Noxious Stimulation Induces Acute Hemorrhage and Impairs Long-Term Recovery after Spinal Cord Injury (SCI) in Female Rats: Evidence Estrous Cycle May Have a Modulatory Effect.

Spinal cord injuries (SCIs) are often the result of traumatic accidents, which also produce multiple other injuries (polytrauma). Nociceptive input from associated injuries has been shown to significantly impair recovery post-SCI. Historically, work in our laboratory has focused exclusively on male animals; however, increasing incidence of SCI in females requires research to determine whether pain (nociceptive) input poses the same risk to their recovery. Some animal studies have shown that females demonstrate greater tissue preservation and better locomotor recovery post-SCI. Given this, we examined the effect of sex on SCI recovery in two pain models—intermittent electrical stimulation (shock) to the tail or capsaicin injection to the hindpaw. Female rats received a lower thoracic contusion injury and were exposed to noxious stimulation the next day. The acute effect of noxious input on cardiovascular function, locomotor performance, and hemorrhage were assessed. Treatment with capsaicin or noxious electrical stimulation disrupted locomotor performance, increased blood pressure, and disrupted stepping. Additional experiments examined the long-term consequences of noxious input, demonstrating that both noxious electrical stimulation and capsaicin impair long-term recovery in female rats. Interestingly, injury had a greater effect on behavioral performance when progesterone and estrogen were low (metestrus). Conversely, nociceptive input led to a greater disruption in locomotor performance and produced a greater rise in blood pressure in animals injured during estrus.

K+/Cl- co-transporter-2 upmodulation: a multi-modal therapy to treat spinal cord injury.

K+/Cl- co-transporter-2 upmodulation: a multi-modal therapy to treat spinal cord injury.

Effect sizes and test-retest reliability of the fMRI-based neurologic pain signature

Identifying biomarkers that predict mental states with large effect sizes and high test-retest reliability is a growing priority for fMRI research. We examined a well-established multivariate brain measure that tracks pain induced by nociceptive input, the Neurologic Pain Signature (NPS). In N = 295 participants across eight studies, NPS responses showed a very large effect size in predicting within-person single-trial pain reports (d = 1.45) and medium effect size in predicting individual differences in pain reports (d = 0.49). The NPS showed excellent short-term (within-day) test-retest reliability (ICC = 0.84, with average 69.5 trials/person). Reliability scaled with the number of trials within-person, with ≥60 trials required for excellent test-retest reliability. Reliability was tested in two additional studies across 5-day (N = 29, ICC = 0.74, 30 trials/person) and 1-month (N = 40, ICC = 0.46, 5 trials/person) test-retest intervals. The combination of strong within-person correlations and only modest between-person correlations between the NPS and pain reports indicate that the two measures have different sources of between-person variance. The NPS is not a surrogate for individual differences in pain reports but can serve as a reliable measure of pain-related physiology and mechanistic target for interventions.

Contribution of Brain Processes to Tissue Loss After Spinal Cord Injury: Does a Pain-Induced Rise in Blood Pressure Fuel Hemorrhage?

Pain (nociceptive) input soon after spinal cord injury (SCI) expands the area of tissue loss (secondary injury) and impairs long-term recovery. Evidence suggests that nociceptive stimulation has this effect because it promotes acute hemorrhage. Disrupting communication with the brain blocks this effect. The current study examined whether rostral systems exacerbate tissue loss because pain input drives an increase in systolic blood pressure (BP) and flow that fuels blood infiltration. Rats received a moderate contusion injury to the lower thoracic (T12) spinal cord. Communication with rostral processes was disrupted by cutting the spinal cord 18 h later at T2. Noxious electrical stimulation (shock) applied to the tail (Experiment 1), or application of the irritant capsaicin to one hind paw (Experiment 2), increased hemorrhage at the site of injury. Shock, but not capsaicin, increased systolic BP and tail blood flow in sham-operated rats. Cutting communication with the brain blocked the shock-induced increase in systolic BP and tail blood flow. Experiment 3 examined the effect of artificially driving a rise in BP with norepinephrine (NE) in animals that received shock. Spinal transection attenuated hemorrhage in vehicle-treated rats. Treatment with NE drove a robust increase in BP and tail blood flow but did not increase the extent of hemorrhage. The results suggest pain input after SCI can engage rostral processes that fuel hemorrhage and drive sustained cardiovascular output. An increase in BP was not, however, necessary or sufficient to drive hemorrhage, implicating other brain-dependent processes.

"Taking action" to reduce pain-Has interpretation of the motor adaptation to pain been too simplistic?

Movement adapts during acute pain. This is assumed to reduce nociceptive input, but the interpretation may not be straightforward. We investigated whether movement adaptation during pain reflects a purposeful search for a less painful solution. Three groups of participants performed two blocks (Baseline, Experimental) of wrist movements in the radial-ulnar direction. For the Control group (n = 10) both blocks were painfree. In two groups, painful electrical stimulation was applied at the elbow in Experimental conditions when the wrist crossed radial-ulnar neutral. Different stimulus intensities were given for specific wrist angles in a secondary direction (flexion-extension) as the wrist passed radial-ulnar neutral (Pain 5–1 group:painful stimulation at ~5 or ~1/10—n = 21; Pain 5–0 group:~5 or 0(no stimulation)/10—n = 6)). Participants were not informed about the less painful alternative and could use any strategy. We recorded the percentage of movements using the wrist flexion/extension alignment that evoked the lower intensity noxious stimulus, movement variability, and change in wrist/forearm alignment during pain. Participants adapted their strategy of wrist movement during pain provocation and reported less pain over time. Three adaptations of wrist movement were observed; (i) greater use of the wrist alignment with no/less noxious input (Pain 5–1, n = 8/21; Pain 5–0, n = 2/6); (ii) small (n = 9/21; n = 3/6) or (iii) large (n = 4/21; n = 1/6) change of wrist/forearm alignment to a region that was not allocated to provide an actual reduction in noxious stimulus. Pain reduction was achieved with “taking action” to relieve pain and did not depend on reduced noxious stimulus.

Hemorrhage and Locomotor Deficits Induced by Pain Input after Spinal Cord Injury Are Partially Mediated by Changes in Hemodynamics.

Nociceptive input diminishes recovery and increases lesion area after a spinal cord injury (SCI). Recent work has linked these effects to the expansion of hemorrhage at the site of injury. The current article examines whether these adverse effects are linked to a pain-induced rise in blood pressure (BP) and/or flow. Male rats with a low-thoracic SCI were treated with noxious input (electrical stimulation [shock] or capsaicin) soon after injury. Locomotor recovery and BP were assessed throughout. Tissues were collected 3 h, 24 h, or 21 days later. Both electrical stimulation and capsaicin undermined locomotor function and increased the area of hemorrhage. Changes in BP/flow varied depending on type of noxious input, with only shock producing changes in BP. Providing behavioral control over the termination of noxious stimulation attenuated the rise in BP and hemorrhage. Pretreatment with the α-1 adrenergic receptor inverse agonist, prazosin, reduced the stimulation-induced rise in BP and hemorrhage. Prazosin also attenuated the adverse effect that noxious stimulation has on long-term recovery. Administration of the adrenergic agonist, norepinephrine 1 day after injury induced an increase in BP and disrupted locomotor function, but had little effect on hemorrhage. Further, inducing a rise in BP/flow using norepinephrine undermined long-term recovery and increased tissue loss. Mediational analyses suggest that the pain-induced rise in blood flow may foster hemorrhage after SCI. Increased BP appears to act through an independent process to adversely affect locomotor performance, tissue sparing, and long-term recovery.

Characterisation of motor cortex organisation in patients with different presentations of persistent low back pain.

Persistence of low back pain is thought to be associated with different underlying pain mechanisms, including ongoing nociceptive input and central sensitisation. We hypothesised that primary motor cortex (M1) representations of back muscles (a measure of motor system adaptation) would differ between pain mechanisms, with more consistent observations in individuals presumed to have an ongoing contribution of nociceptive input consistently related to movement/posture. We tested 28 participants with low back pain sub-grouped by the presumed underlying pain mechanisms: nociceptive pain, nociplastic pain and a mixed group with features consistent with both. Transcranial magnetic stimulation was used to study M1 organisation of back muscles. M1 maps of multifidus (deep and superficial) and longissimus erector spinae were recorded with fine-wire electromyography and thoracic erector spinae with surface electromyography. The nociplastic pain group had greater variability in M1 map location (centre of gravity) than other groups (p < .01), which may suggest less consistency, and perhaps relevance, of motor cortex adaptation for that group. The mixed group had greater overlap of M1 representations between deep/superficial muscles than nociceptive pain (deep multifidus/longissimus: p = .001, deep multifidus/thoracic erector spinae: p = .008) and nociplastic pain (deep multifidus/longissimus: p = .02, deep multifidus/thoracic erector spinae: p = .02) groups. This study provides preliminary evidence of differences in M1 organisation in subgroups of low back pain classified by likely underlying pain mechanisms. Despite the sample size, differences in cortical re-organisation between subgroups were detected. Differences in M1 organisation in subgroups of low back pain supports tailoring of treatment based on pain mechanism and motor adaptation.

5-hydroxytryptamine in migraine: The puzzling role of ionotropic 5-HT3 receptor in the context of established therapeutic effect of metabotropic 5-HT1 subtypes.

5-hydroxytryptamine (5-HT; serotonin) is traditionally considered as a key mediator implicated in migraine. Multiple 5-HT receptor subtypes contribute to a variety of region-specific functional effects. The raphé nuclei control nociceptive inputs by releasing 5-HT in the brainstem, whereas dural mast cells provide the humoral source of 5-HT in the meninges. Triptans (5-HT1B/D agonists) and ditans (5-HT1F agonists) are the best established 5-HT anti-migraine agents. However, activation of meningeal afferents via ionotropic 5-HT3 receptors results in long-lasting excitatory drive suggesting a pro-nociceptive role for these receptors in migraine. Nevertheless, clinical data do not clearly support the applicability of currently available 5-HT3 antagonists to migraine treatment. The reasons for this might be the presence of 5-HT3 receptors on inhibitory interneurons dampening the excitatory drive, a lack of 5-HT3 A-E subunit-selective antagonists and gender/age-dependent effects. This review is focusing on the controversial role of 5-HT3 receptors in migraine pathology and related pharmacological perspectives of 5-HT ligands. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Do "central sensitization" questionnaires reflect measures of nociceptive sensitization or psychological constructs? Protocol for a systematic review.

Central sensitization (CS) was first defined in animal studies to be increased nociceptive responsiveness due to sensitization of neurons in the central nervous system, usually the result of prolonged nociceptive input or a disease state. Recently, the concept of CS has been adopted in clinical assessments of chronic pain, but its diagnosis in humans has expanded to include the enhancement of a wide range of nociceptive, sensory, and emotional responses. Many poorly understood pain disorders are referred to as "central sensitivity syndrome," a term associated with a broad range of hypervigilant sensory and emotional responses. Diagnosis often involves a review of medical records and an assessment of behaviour, emotional disposition, and overall sensitivity of a patient. Obviously, these assessments are unable to directly capture the responsiveness of nociceptive neurons. The purpose of this review is to ascertain whether self-report questionnaires associated with central sensitization and the diagnosis of central sensitivity syndrome are associated with enhanced nociceptive responses or whether they more validly measure sensitivity in a broader sense (ie, including emotional responses). Following the PRISMA guidelines, a detailed search of studies that involve the Central Sensitization Inventory or Pain Sensitivity Questionnaire correlated with either nociceptive sensory tests (quantitative sensory testing) or emotional hypervigilance (anxiety, depression, stress, etc) will be conducted on MEDLINE, PsychINFO, and Web of Science. The review is expected to synthesize correlations between sensitivity questionnaires and nociceptive or emotional sensitivity to determine whether these questionnaires reflect a broadened understanding of the term "central sensitization."