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Drug treatments for pain often do not outperform placebo, and a better understanding of placebo mechanisms is needed to improve treatment development and clinical practice. In a large-scale fMRI study ( N  = 392) with pre-registered analyses, we tested whether placebo analgesic treatment modulates nociceptive processes, and whether its effects generalize from conditioned to unconditioned pain modalities. Placebo treatment caused robust analgesia in conditioned thermal pain that generalized to unconditioned mechanical pain. However, placebo did not decrease pain-related fMRI activity in brain measures linked to nociceptive pain, including the Neurologic Pain Signature (NPS) and spinothalamic pathway regions, with strong support for null effects in Bayes Factor analyses. In addition, surprisingly, placebo increased activity in some spinothalamic regions for unconditioned mechanical pain. In contrast, placebo reduced activity in a neuromarker associated with higher-level contributions to pain, the Stimulus Intensity Independent Pain Signature (SIIPS), and affected activity in brain regions related to motivation and value, in both pain modalities. Individual differences in behavioral analgesia were correlated with neural changes in both modalities. Our results indicate that cognitive and affective processes primarily drive placebo analgesia, and show the potential of neuromarkers for separating treatment influences on nociception from influences on evaluative processes. The mechanisms underlying placebo analgesia are not fully understood. Here the authors show that a placebo treatment inducing analgesia in healthy participants reduced fMRI activity in systems related to evaluative and affective processes, but not systems related to nociceptive pain processing.

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 1 , 2 . 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 3 . 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 4 , 5 . 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. Studies using mouse and non-human primate models identify the innate immune regulator STING—acting via type I interferons—as a key regulator of nociception, suggesting new targets for the treatment of chronic pain.

ObjectiveAn 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.MethodsAntibodies 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.ResultsMice 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.ConclusionsThe 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.

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.

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’.

IntroductionThe pharmacological block of the greater occipital nerve has been proven effective in numerous headache and facial pain syndromes. This clinical effect supports the hypothesis of a strong functional interaction between the occipital and trigeminal nerves which has been proposed in neurophysiological in vivo experiments in rodents. Although it is likely that the interaction has to occur in the central nervous system, the exact site and the mechanisms of the interaction remain largely unknown.MethodsFocusing on these questions we investigated in a double-blind, placebo-controlled, randomised study the influence of an occipital nerve block with lidocaine 1% on neuronal activation in the trigeminocervical complex using high-resolution functional magnetic resonance on a 3T scanner. In order to investigate potential clinical effects on the trigeminal nerve, we further performed quantitative sensory testing and analysed a potential shift in thermal detection and pain thresholds.ResultsThe pharmacological block of the greater occipital nerve induced an occipital anaesthesia ipsilateral to the block. Functional imaging revealed that the occipital injection of lidocaine but not placebo significantly reduced nociceptive trigeminal activation.ConclusionsThese data suggest that the functional inhibition of the occipital nerve block on trigeminal nociceptive activity is likely to occur at the C2 level where the occipital nerve enters the trigeminocervical complex and converges on the same central nuclei before the signal crosses the midline at that level and is then transmitted to higher processing centres.

The integration of somatosensory information is generally assumed to be a function of the central nervous system (CNS). Here we describe fully functional GABAergic communication within rodent peripheral sensory ganglia and show that it can modulate transmission of pain-related signals from the peripheral sensory nerves to the CNS. We found that sensory neurons express major proteins necessary for GABA synthesis and release and that sensory neurons released GABA in response to depolarization. In vivo focal infusion of GABA or GABA reuptake inhibitor to sensory ganglia dramatically reduced acute peripherally induced nociception and alleviated neuropathic and inflammatory pain. In addition, focal application of GABA receptor antagonists to sensory ganglia triggered or exacerbated peripherally induced nociception. We also demonstrated that chemogenetic or optogenetic depolarization of GABAergic dorsal root ganglion neurons in vivo reduced acute and chronic peripherally induced nociception. Mechanistically, GABA depolarized the majority of sensory neuron somata, yet produced a net inhibitory effect on the nociceptive transmission due to the filtering effect at nociceptive fiber T-junctions. Our findings indicate that peripheral somatosensory ganglia represent a hitherto underappreciated site of somatosensory signal integration and offer a potential target for therapeutic intervention.

Chemically induced nociception has not yet been studied intensively in genetically tractable models. Hence, our goal was to establish a Drosophila assay that can be used to study the cellular and molecular/genetic bases of chemically induced nociception. Drosophila 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 Drosophila larvae. This assay, combined with the high genetic resolving power of Drosophila, 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’.

Dexmedetomidine decreases heart rate (HR) and increases high frequency (HF) component of HR variability (HRV). Analgesia Nociception Index (ANI) measures nociception by analyzing the influence of respiration on HF component of HRV while surgical pleth index (SPI) derives this information from photoplethymographic signals of finger arterioles. Therefore, during administration of dexmedetomidine, reliability of ANI may vary. This study compared the changes in ANI, SPI and hemodynamics (HR and mean arterial pressure [MAP]) during various noxious stimuli with fentanyl and dexmedetomidine intraoperative analgesia. In this trial, patients undergoing elective supratentorial surgery under general anesthesia were randomized to receive either fentanyl or dexmedetomidine infusion for intraoperative analgesia. ANI (instantaneous and mean), SPI, HR and MAP were compared before and after noxious stimuli (intubation, skull pin insertion, skin incision and craniotomy) with respect to magnitude of maximum change in the variable and the time taken for the maximal change (defined as response time) between the groups. A total of 58 patients, 29 in each group were recruited into the study. At intubation, SPI changed significantly more in the fentanyl group compared to dexmedetomidine group (37 versus 20 units, p  = 0.007). At skull pinning, ANI values (both instantaneous and mean) changed more in dexmedetomidine group ( p  = 0.024 and 0.009) with significantly longer response time ( p  = 0.039). There was no difference between the groups with respect to any of the variables at skin incision and craniotomy. ANI during use of dexmedetomidine and SPI while using fentanyl, might be the better choices as intraoperative nociception monitors.