The innate immune regulator STING is a critical sensor of self- and pathogen-derived DNA. DNA sensing by STING leads to the induction of type-I interferons (IFN-I) and other cytokines, which promote ...immune-cell-mediated eradication of pathogens and neoplastic cells
. STING is also a robust driver of antitumour immunity, which has led to the development of STING activators and small-molecule agonists as adjuvants for cancer immunotherapy
. Pain, transmitted by peripheral nociceptive sensory neurons (nociceptors), also aids in host defence by alerting organisms to the presence of potentially damaging stimuli, including pathogens and cancer cells
. Here we demonstrate that STING is a critical regulator of nociception through IFN-I signalling in peripheral nociceptors. We show that mice lacking STING or IFN-I signalling exhibit hypersensitivity to nociceptive stimuli and heightened nociceptor excitability. Conversely, intrathecal activation of STING produces robust antinociception in mice and non-human primates. STING-mediated antinociception is governed by IFN-Is, which rapidly suppress excitability of mouse, monkey and human nociceptors. Our findings establish the STING-IFN-I signalling axis as a critical regulator of physiological nociception and a promising new target for treating chronic pain.
The majority of postoperative patients report moderate to severe pain, possibly related to opioid underdosing or overdosing during surgery. Objective guidance of opioid dosing using the Nociception ...Level (NOL) index, a multiparameter artificial intelligence-driven index designed to monitor nociception during surgery, may lead to a more appropriate analgesic regimen, with effects beyond surgery. We tested whether NOL-guided opioid dosing during general anaesthesia results in less postoperative pain.
In this two-centre RCT, 50 patients undergoing abdominal surgery under fentanyl/sevoflurane anaesthesia were randomised to NOL-guided fentanyl dosing or standard care in which fentanyl dosing was based on haemodynamics. The primary endpoint of the study was postoperative pain assessed in the PACU.
Median postoperative pain scores were 3.2 (inter-quartile range 1.3–4.3) and 4.8 (3.0–5.3) in NOL-guided and standard care groups, respectively (P=0.006). Postoperative morphine consumption (standard deviation) was 0.06 (0.07) mg kg−1 (NOL-guided group) and 0.09 (0.09) mg kg−1 (control group; P=0.204). During surgery, fentanyl dosing was not different between groups (NOL-guided group: 6.4 4.2 μg kg−1vs standard care: 6.0 2.2 μg kg−1, P=0.749), although the variation between patients was greater in the NOL-guided group (% coefficient of variation 66% in the NOL-guided group vs 37% in the standard care group).
Despite absence of differences in fentanyl and morphine consumption during and after surgery, a 1.6-point improvement in postoperative pain scores was observed in the NOL-guided group. We attribute this to NOL-driven rather than BP- and HR-driven fentanyl dosing during anaesthesia.
www.trialregister.nl under identifier NL7845.
Nociception, in contrast to pain, is not a subjective feeling, but the physiological encoding and processing of nociceptive stimuli. However, monitoring nociception remains a challenge in attempts to ...lower the incidence of acute postoperative pain and the move towards a more automated approach to analgesia and anaesthesia. To date, several commercialised devices promise a more accurate reflection of nociception than the traditionally used vital signs, blood pressure and heart rate. This narrative review presents an overview of existing technologies and commercially available devices, and offers a perspective for future research. Although firm conclusions about individual methods may be premature, none currently appears to offer a sufficiently broad applicability. Furthermore, there is currently no firm evidence for any clinically relevant influence of such devices on patient outcome. However, the available monitors have significantly aided the understanding of underlying mechanisms and identification of potential pitfalls.
An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) ...where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation.
Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin.
Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin.
The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.
Nociception monitoring devices are designed to estimate nociception during general anaesthesia. We evaluated the predictive accuracy of heart rate and three nociception indices to predict ...postoperative pain before emergence from general anaesthesia.
In patients undergoing trauma or orthopaedic surgery, HR, Surgical Pleth Index® (SPI), Pupillary Pain Index® (PPI), and Nociception Level® (NOL) were simultaneously recorded for 5 min after the end of surgery but before return of consciousness. After admission to the recovery room, pain scores were assessed regularly for 2 h. HR, SPI, PPI, and NOL were analysed for their predictive accuracy of postoperative pain and opioid consumption with assessment of area under the receiver operating characteristic (AUC) curves, Spearman rank-correlation coefficient, and regression modelling.
Data for 60 subjects were analysed. The AUC (95% confidence interval 95% CI) of the predictive accuracy for moderate-to-severe postoperative pain differed between nociception indices (HR=0.46 0.29–0.64, P=0.671; SPI=0.46 0.31–0.61, P=0.621; PPI=0.52 0.36–0.68, P=0.770; NOL=0.66 0.51–0.81, P=0.038). In a multivariable logistic regression model, a higher predictive accuracy was found for a multivariable predictor combining NOL values with ASA physical status and information about use of regional anaesthesia (AUC=0.83 0.72–0.94, P<0.001).
Heart rate, Surgical Pleth Index, Pupillary Pain Index, and Nociception Level measured before emergence from general anaesthesia do not yet have sufficient diagnostic accuracy for prediction of postoperative pain.
NCT05063227.
G protein-coupled receptors (GPCRs) are considered to function primarily at the plasma membrane, where they interact with extracellular ligands and couple to G proteins that transmit intracellular ...signals. Consequently, therapeutic drugs are designed to target GPCRs at the plasma membrane. Activated GPCRs undergo clathrin-dependent endocytosis. Whether GPCRs in endosomes control pathophysiological processes in vivo and are therapeutic targets remains uncertain. We investigated the contribution of endosomal signaling of the calcitonin receptor-like receptor (CLR) to pain transmission. Calcitonin gene-related peptide (CGRP) stimulated CLR endocytosis and activated protein kinase C (PKC) in the cytosol and extracellular signal regulated kinase (ERK) in the cytosol and nucleus. Inhibitors of clathrin and dynamin prevented CLR endocytosis and activation of cytosolic PKC and nuclear ERK, which derive from endosomal CLR. A cholestanol-conjugated antagonist, CGRP8–37, accumulated in CLR-containing endosomes and selectively inhibited CLR signaling in endosomes. CGRP caused sustained excitation of neurons in slices of rat spinal cord. Inhibitors of dynamin, ERK, and PKC suppressed persistent neuronal excitation. CGRP8–37–cholestanol, but not unconjugated CGRP8–37, prevented sustained neuronal excitation. When injected intrathecally to mice, CGRP8–37–cholestanol inhibited nociceptive responses to intraplantar injection of capsaicin, formalin, or complete Freund’s adjuvant more effectively than unconjugated CGRP8–37. Our results show that CLR signals from endosomes to control pain transmission and identify CLR in endosomes as a therapeutic target for pain. Thus, GPCRs function not only at the plasma membrane but also in endosomes to control complex processes in vivo. Endosomal GPCRs are a drug target that deserve further attention.
Toll-like receptors in chronic pain Nicotra, Lauren; Loram, Lisa C.; Watkins, Linda R. ...
Experimental neurology,
04/2012, Letnik:
234, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Proinflammatory central immune signaling contributes significantly to the initiation and maintenance of heightened pain states. Recent discoveries have implicated the innate immune system, pattern ...recognition Toll-like receptors in triggering these proinflammatory central immune signaling events. These exciting developments have been complemented by the discovery of neuronal expression of Toll-like receptors, suggesting pain pathways can be activated directly by the detection of pathogen associated molecular patterns or danger associated molecular patterns. This review will examine the evidence to date implicating Toll-like receptors and their associated signaling components in heightened pain states. In addition, insights into the impact Toll-like receptors have on priming central immune signaling systems for heightened pain states will be discussed. The influence possible sex differences in Toll-like receptor signaling have for female pain and the recognition of small molecule xenobiotics by Toll-like receptors will also be reviewed.
► Proinflammatory central immune signaling contributes to chronic pain. ► Toll-like receptors are now recognized to contribute to the chronic pain process. ► Recent evidence shows neuronal Toll-like receptor expression and activation. ► This review examines Toll-like receptors in chronic pain and xenobiotic recognition.
Abstract Background The mesolimbic reward system plays a critical role in modulating nociception; however, its underlying molecular, cellular, and neural circuitry mechanisms remain unknown. Methods ...Chronic constrictive injury (CCI) of the sciatic nerve was used to model neuropathic pain. Projection-specific in vitro recordings in mouse brain slices and in vivo recordings from anesthetized animals were used to measure firing of dopaminergic (DA) neurons in the ventral tegmental area (VTA). The role of VTA−nucleus accumbens (NAc) circuitry in nociceptive regulation was assessed using optogenetic and pharmacological manipulations, and the underlying molecular mechanisms were investigated by Western blotting, enzyme-linked immunosorbent assays, and conditional knockdown techniques. Results c-Fos expression in and firing of contralateral VTA−NAc DA neurons were elevated in CCI mice, and optogenetic inhibition of these neurons reversed CCI-induced thermal hyperalgesia. CCI increased the expression of brain-derived neurotrophic factor (BDNF) protein but not mRNA in the contralateral NAc. This increase was reversed by pharmacological inhibition of VTA DA neuron activity, which induced an antinociceptive effect that was neutralized by injecting exogenous BDNF into the NAc. Moreover, inhibition of BDNF synthesis in the VTA with anisomycin or selective knockdown of BDNF in the VTA−NAc pathway were antinociceptive in CCI mice. Conclusions These results reveal a novel mechanism of nociceptive modulation in the mesolimbic reward circuitry and provide new insight into the neural circuits involved in the processing of nociceptive information.
The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive behavior, pain, and multiple ...aspects of autonomic control, including respiration, blood pressure, water balance, and thermoregulation. Outputs are known to be similarly widespread and complex. How sensory information is handled in PBN and used to inform different outputs to maintain homeostasis and promote survival is only now being elucidated. With a focus on taste and ingestive behaviors, pain, and thermoregulation, this review is intended to provide a context for analysis of PBN circuits involved in aversion and avoidance, and consider how information of various modalities, interoceptive and exteroceptive, is processed within PBN and transmitted to distinct targets to signal challenge, and to engage appropriate behavioral and physiological responses to maintain homeostasis.
Key points
Deep continuous theta burst stimulation (cTBS) of the right operculo‐insular cortex delivered with a double cone coil selectively impairs the ability to perceive thermonociceptive input ...conveyed by Aδ‐fibre thermonociceptors without concomitantly affecting the ability to perceive innocuous warm, cold or vibrotactile sensations.
Unlike deep cTBS, superficial cTBS of the right operculum delivered with a figure‐of‐eight coil does not affect the ability to perceive thermonociceptive input conveyed by Aδ‐fibre thermonociceptors.
The effect of deep operculo‐insular cTBS on the perception of Aδ‐fibre input was present at both the contralateral and the ipsilateral hand.
The magnitude of the increase in Aδ‐heat detection threshold induced by the deep cTBS was significantly correlated with the intensity of the cTBS pulses.
Deep cTBS delivered over the operculo‐insular cortex is associated with a risk of transcranial magnetic stimulation‐induced seizure.
Previous studies have suggested a pivotal role of the insular cortex in nociception and pain perception. Using a double‐cone coil designed for deep transcranial magnetic stimulation, our objective was to assess (1) whether continuous theta burst stimulation (cTBS) of the operculo‐insular cortex affects differentially the perception of different types of thermal and mechanical somatosensory inputs, (2) whether the induced after‐effects are lateralized relative to the stimulated hemisphere, and (3) whether the after‐effects are due to neuromodulation of the insula or neuromodulation of the more superficial opercular cortex. Seventeen participants took part in two experiments. In Experiment 1, thresholds and perceived intensity of Aδ‐ and C‐fibre heat pain elicited by laser stimulation, non‐painful cool sensations elicited by contact cold stimulation and mechanical vibrotactile sensations were assessed at the left hand before, immediately after and 20 min after deep cTBS delivered over the right operculo‐insular cortex. In Experiment 2, Aδ‐fibre heat pain and vibrotactile sensations elicited by stimulating the contralateral and ipsilateral hands were evaluated before and after deep cTBS or superficial cTBS delivered using a flat figure‐of‐eight coil. Only the threshold to detect Aδ‐fibre heat pain was significantly increased 20 min after deep cTBS. This effect was present at both hands. No effect was observed after superficial cTBS. Neuromodulation of the operculo‐insular cortex using deep cTBS induces a bilateral reduction of the ability to perceive Aδ‐fibre heat pain, without concomitantly affecting the ability to perceive innocuous warm, cold or vibrotactile sensations.
Key points
Deep continuous theta burst stimulation (cTBS) of the right operculo‐insular cortex delivered with a double cone coil selectively impairs the ability to perceive thermonociceptive input conveyed by Aδ‐fibre thermonociceptors without concomitantly affecting the ability to perceive innocuous warm, cold or vibrotactile sensations.
Unlike deep cTBS, superficial cTBS of the right operculum delivered with a figure‐of‐eight coil does not affect the ability to perceive thermonociceptive input conveyed by Aδ‐fibre thermonociceptors.
The effect of deep operculo‐insular cTBS on the perception of Aδ‐fibre input was present at both the contralateral and the ipsilateral hand.
The magnitude of the increase in Aδ‐heat detection threshold induced by the deep cTBS was significantly correlated with the intensity of the cTBS pulses.
Deep cTBS delivered over the operculo‐insular cortex is associated with a risk of transcranial magnetic stimulation‐induced seizure.
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