Offset analgesia is associated with opposing modulation of medial versus dorsolateral prefrontal cortex activations: A functional near-infrared spectroscopy study.

Offset analgesia is defined by a dramatic drop in perceived pain intensity with a relatively small decrease in noxious input. Although functional magnetic resonance imaging studies implicate subcortical descending inhibitory circuits during offset analgesia, the role of cortical areas remains unclear. The current study identifies cortical correlates of offset analgesia using functional near infrared spectroscopy (fNIRS). Twenty-four healthy volunteers underwent fNIRS scanning during offset (OS) and control (Con) heat stimuli applied to the forearm. After controlling for non-neural hemodynamic responses in superficial tissues, widespread increases in cortical oxygenated hemoglobin concentration were observed, reflecting cortical activation during heat pain. OS-Con contrasts revealed deactivations in bilateral medial prefrontal cortex (mPFC) and bilateral somatosensory cortex (SSC) associated with offset analgesia. Right dorsolateral prefrontal cortex (dlPFC) showed activation only during OS. These data demonstrate opposing cortical activation patterns during offset analgesia and support a model in which right dlPFC underlies ongoing evaluation of pain intensity change. With predictions of decreasing pain intensity, right dlPFC activation likely inhibits ascending noxious input via subcortical pathways resulting in SSC and mPFC deactivation. This study identifies cortical circuitry underlying offset analgesia and introduces the use of fNIRS to study pain modulation in an outpatient clinical environment.

ERK2 Alone Drives Inflammatory Pain But Cooperates with ERK1 in Sensory Neuron Survival.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are highly homologous yet distinct components of signal transduction pathways known to regulate cell survival and function. Recent evidence indicates an isoform-specific role for ERK2 in pain processing and peripheral sensitization. However, the function of ERK2 in primary sensory neurons has not been directly tested. To dissect the isoform-specific function of ERK2 in sensory neurons, we used mice with Cre-loxP-mediated deletion of ERK2 in Nav1.8(+) sensory neurons that are predominantly nociceptors. We find that ERK2, unlike ERK1, is required for peripheral sensitization and cold sensation. We also demonstrate that ERK2, but not ERK1, is required to preserve epidermal innervation in a subset of peptidergic neurons. Additionally, deletion of both ERK isoforms in Nav1.8(+) sensory neurons leads to neuron loss not observed with deletion of either isoform alone, demonstrating functional redundancy in the maintenance of sensory neuron survival. Thus, ERK1 and ERK2 exhibit both functionally distinct and redundant roles in sensory neurons. SIGNIFICANCE STATEMENT: ERK1/2 signaling affects sensory neuron function and survival. However, it was not clear whether ERK isoform-specific roles exist in these processes postnatally. Previous work from our laboratory suggested either functional redundancy of ERK isoforms or a predominant role for ERK2 in pain; however, the tools to discriminate between these possibilities were not available at the time. In the present study, we use new genetic knock-out lines to demonstrate that ERK2 in sensory neurons is necessary for development of inflammatory pain and for postnatal maintenance of peptidergic epidermal innervation. Interestingly, postnatal loss of both ERK isoforms leads to a profound loss of sensory neurons. Therefore, ERK1 and ERK2 display both functionally distinct and redundant roles in sensory neurons.

Hierarchical Clustering Applied to Chronic Pain Drawings Identifies Undiagnosed Fibromyalgia: Implications for Busy Clinical Practice.

Currently-used assessments for fibromyalgia require clinicians to suspect a fibromyalgia diagnosis, a process susceptible to unintentional bias. Automated assessments of standard patient-reported outcomes (PROs) could be used to prompt formal assessments, potentially reducing bias. We sought to determine whether hierarchical clustering of patient-reported pain distribution on digital body map drawings predicted fibromyalgia diagnosis. Using an observational cohort from the University of Pittsburgh's Patient Outcomes Repository for Treatment registry, which contains PROs and electronic medical record data from 21,423 patients (March 17, 2016-June 25, 2019) presenting to pain management clinics, we tested the hypothesis that hierarchical clustering subgroup was associated with fibromyalgia diagnosis, as determined by ICD-10 code. Logistic regression revealed a significant relationship between the body map cluster subgroup and fibromyalgia diagnosis. The cluster subgroup with the most body areas selected was the most likely to receive a diagnosis of fibromyalgia when controlling for age, gender, anxiety, and depression. Despite this, more than two-thirds of patients in this cluster lacked a clinical fibromyalgia diagnosis. In an exploratory analysis to better understand this apparent underdiagnosis, we developed and applied proxies of fibromyalgia diagnostic criteria. We found that proxy diagnoses were more common than ICD-10 diagnoses, which may be due to less frequent clinical fibromyalgia diagnosis in men. Overall, we find evidence of fibromyalgia underdiagnosis, likely due to gender bias. Coupling PROs that take seconds to complete, such as a digital pain body map, with machine learning is a promising strategy to reduce bias in fibromyalgia diagnosis and improve patient outcomes. PERSPECTIVE: This investigation applies hierarchical clustering to patient-reported, digital pain body maps, finding an association between body map responses and clinical fibromyalgia diagnosis. Rapid, computer-assisted interpretation of pain body maps would be clinically useful in prompting more detailed assessments for fibromyalgia, potentially reducing gender bias.

Genetic targeting of ERK1 suggests a predominant role for ERK2 in murine pain models.

The extracellular signal-regulated kinase (ERK) isoforms, ERK1 and ERK2, are believed to be key signaling molecules in nociception and nociceptive sensitization. Studies using inhibitors targeting the shared ERK1/2 upstream activator, mitogen-activated protein kinase kinase (MEK), and transgenic mice expressing a dominant-negative form of MEK have established the importance of ERK1/2 signaling. However, these techniques do not discriminate between ERK1 and ERK2. To dissect the function of each isoform in pain, we used mice with a targeted genetic deletion of ERK1 [ERK1 knock-out (KO)] to test the hypothesis that ERK1 is required for behavioral sensitization in rodent pain models. Despite activation (phosphorylation) of ERK1 after acute noxious stimulation and in models of chronic pain, we found that ERK1 was not required for formalin-induced spontaneous behaviors, complete Freund's adjuvant-induced heat and mechanical hypersensitivity, and spared nerve injury-induced mechanical hypersensitivity. However, ERK1 deletion did delay formalin-induced long-term heat hypersensitivity, without affecting formalin-induced mechanical hypersensitivity, suggesting that ERK1 partially shapes long-term responses to formalin. Interestingly, ERK1 deletion resulted in elevated basal ERK2 phosphorylation. However, this did not appear to influence nociceptive processing, since inflammation-induced ERK2 phosphorylation and pERK1/2 immunoreactivity in spinal cord were not elevated in ERK1 KO mice. Additionally, systemic MEK inhibition with SL327 (alpha-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile) attenuated formalin-induced spontaneous behaviors similarly in wild-type and ERK1 KO mice, indicating that unrelated signaling pathways do not functionally compensate for the loss of ERK1. Together, these results suggest that ERK1 plays a limited role in nociceptive sensitization and support a predominant role for ERK2 in these processes.

Hierarchical clustering by patient-reported pain distribution alone identifies distinct chronic pain subgroups differing by pain intensity, quality, and clinical outcomes.

BACKGROUND: In clinical practice, the bodily distribution of chronic pain is often used in conjunction with other signs and symptoms to support a diagnosis or treatment plan. For example, the diagnosis of fibromyalgia involves tallying the areas of pain that a patient reports using a drawn body map. It remains unclear whether patterns of pain distribution independently inform aspects of the pain experience and influence patient outcomes. The objective of the current study was to evaluate the clinical relevance of patterns of pain distribution using an algorithmic approach agnostic to diagnosis or patient-reported facets of the pain experience. METHODS AND FINDINGS: A large cohort of patients (N = 21,658) completed pain body maps and a multi-dimensional pain assessment. Using hierarchical clustering of patients by body map selection alone, nine distinct subgroups emerged with different patterns of body region selection. Clinician review of cluster body maps recapitulated some clinically-relevant patterns of pain distribution, such as low back pain with radiation below the knee and widespread pain, as well as some unique patterns. Demographic and medical characteristics, pain intensity, pain impact, and neuropathic pain quality all varied significantly across cluster subgroups. Multivariate modeling demonstrated that cluster membership independently predicted pain intensity and neuropathic pain quality. In a subset of patients who completed 3-month follow-up questionnaires (N = 7,138), cluster membership independently predicted the likelihood of improvement in pain, physical function, and a positive overall impression of change related to multidisciplinary pain care. CONCLUSIONS: This study reports a novel method of grouping patients by pain distribution using an algorithmic approach. Pain distribution subgroup was significantly associated with differences in pain intensity, impact, and clinically relevant outcomes. In the future, algorithmic clustering by pain distribution may be an important facet in chronic pain biosignatures developed for the personalization of pain management.

Onset hyperalgesia and offset analgesia: Transient increases or decreases of noxious thermal stimulus intensity robustly modulate subsequent perceived pain intensity.

Reported pain intensity depends not only on stimulus intensity but also on previously experienced pain. A painfully hot temperature applied to the skin evokes a lower subjective pain intensity if immediately preceded by a higher temperature, a phenomenon called offset analgesia. Previous work indicated that prior pain experience can also increase subsequent perceived pain intensity. Therefore, we examined whether a given noxious stimulus is experienced as more intense when it is preceded by an increase from a lower temperature. Using healthy volunteer subjects, we observed a disproportionate increase in pain intensity at a given stimulus intensity when this intensity is preceded by a rise from a lower intensity. This disproportionate increase is similar in magnitude to that of offset analgesia. We call this effect onset hyperalgesia. Control stimuli, in which a noxious temperature is held constant, demonstrate that onset hyperalgesia is distinct from receptor or central sensitization. The absolute magnitudes of offset analgesia and onset hyperalgesia correlate with each other but not with the noxious stimulus temperature. Finally, the magnitude of both offset analgesia and onset hyperalgesia depends on preceding temperature changes. Overall, this study demonstrates that the perceptual effect of a noxious thermal stimulus is influenced in a bidirectional manner depending upon both the intensity and direction of change of the immediately preceding thermal stimulus.

Test-Retest and Inter-Examiner Reliability of a Novel Bedside Quantitative Sensory Testing Battery in Postherpetic Neuralgia Patients.

In health and disease, the somatosensory system has been interrogated with standardized research techniques, collectively referred to as quantitative sensory testing (QST). In neuropathic pain, QST has been used to characterize multiple sensory derangements. However, the use of QST outside the lab has been limited by several factors, including a lack of standardization, variability in procedural technique, and duration of testing that would be unacceptable for clinic. To address these shortcomings, the Neuropathic Pain Research Consortium designed an easy and low-cost "bedside" QST procedure. To test the hypothesis that this procedure would be clinically reliable over time and across different examiners, a multisite, blinded study was performed in subjects with postherpetic neuralgia. Generally, agreement between 2 examiners and over 2 study visits with 1 examiner was high. Additionally, intraclass correlation coefficients and Kappa statistics calculated showed that the battery of QST tests included were highly reliable. Interestingly, mechanical modalities (light brush, pinprick, pressure, and vibration) showed the highest reliability. The least reliable modalities were cool (room temperature) and warmth (38°C). These data demonstrate that the Neuropathic Pain Research Consortium beside QST protocol is reliable across examiner and over time, providing a validated QST tool for use in clinical practice and clinical trials. PERSPECTIVE: This blinded, multicenter trial in 32 patients with postherpetic neuralgia demonstrates bedside QST is reliable and suitable as a clinical trial outcome. The novel bedside battery could be used in clinical trials or in clinical practice over time given the reliability data presented in this article.

Metabotropic glutamate receptor 5 modulates nociceptive plasticity via extracellular signal-regulated kinase-Kv4.2 signaling in spinal cord dorsal horn neurons.

Metabotropic glutamate receptors (mGluRs) play important roles in the modulation of nociception. The group I mGluRs (mGlu1 and mGlu5) modulate nociceptive plasticity via activation of extracellular signal-regulated kinase (ERK) signaling. We reported recently that the K+ channel Kv4.2 subunit underlies A-type K+ currents in the spinal cord dorsal horn and is modulated by the ERK signaling pathway. Kv4.2-mediated A-type currents are important determinants of dorsal horn neuronal excitability and central sensitization that underlies hypersensitivity after tissue injury. In the present study, we demonstrate that ERK-mediated phosphorylation of Kv4.2 is downstream of mGlu5 activation in spinal cord dorsal horn neurons. Activation of group I mGluRs inhibited Kv4.2-mediated A-type K+ currents and increased neuronal excitability in dorsal horn neurons. These effects were mediated by activation of mGlu5, but not mGlu1, and were dependent on ERK activation. Analysis of Kv4.2 phosphorylation site mutants clearly identified S616 as the residue responsible for mGlu5-ERK-dependent modulation of A-type currents and excitability. Furthermore, nociceptive behavior induced by activation of spinal group I mGluRs was impaired in Kv4.2 knock-out mice, demonstrating that, in vivo, modulation of Kv4.2 is downstream of mGlu5 activation. Altogether, our results indicate that activation of mGlu5 leads to ERK-mediated phosphorylation and modulation of Kv4.2-containing potassium channels in dorsal horn neurons. This modulation may contribute to nociceptive plasticity and central sensitization associated with chronic inflammatory pain conditions.

Hotheaded: TRPV1 as mediator of hippocampal synaptic plasticity.

TRPV1 is a sensory transduction channel that mediates thermal nociception and some aspects of pathological pain. In this issue of Neuron, Gibson et al. report that TRPV1 also plays important roles in hippocampal synaptic plasticity, presenting a potential challenge for TRPV1-targeted therapeutics for the treatment of pain.

Alpha-synuclein protects naive but not dbcAMP-treated dopaminergic cell types from 1-methyl-4-phenylpyridinium toxicity.

The pre-synaptic protein, alpha-synuclein, has been associated with the pathogenesis of Parkinson's disease. The present study indicates that alpha-synuclein, but not its mutants (A53T, A30P), can protect CNS dopaminergic cells from the parkinsonism-inducing drug 1-methyl-4-phenylpyridinium (MPP+), whereas it cannot protect from the dopaminergic toxin, 6-hydroxydopamine, hydrogen-peroxide, or the beta-amyloid peptide, A-beta. Protection from MPP+ was directly correlated with the preservation of mitochondrial function. Specifically, alpha-synuclein rescued cells from MPP+ mediated decreases in mitochondrial dehydrogenase activity and loss of ATP levels by utilizing ketosis. It also prevented toxin-induced activation of the creatine kinase/creatine phosphate system. Similarly, alpha-synuclein protected cells from the complex I inhibitor rotenone and 3-nitroproprionic acid, a complex II inhibitor. Wild-type alpha-synuclein-mediated neuroprotection and subsequent alterations in energy were not found in dbcAMP-differentiated cells. These results suggest that the normal physiological role for alpha-synuclein may change during development.