Papers of the Week

Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor-positive (MOR) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR neurons in the mPFC are monosynaptically connected and directly inhibit layer V pyramidal neurons that project to the vlPAG via GABA receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Our results shed light on the fundamental neurobiological mechanism of the placebo effect that maximizes therapeutic efficacy and reduces adverse drug effects in medical practice.

A significant number of patients develop chronic pain after surgery, but prediction of those who are at risk is currently not possible. Thus, prognostic prediction models that include bio-psycho, social and physiological factors in line with the complex nature of chronic pain would be urgently required. Here, we performed a translational study in male volunteers before an experimental incision injury. We determined multi-modal factors ranging from pain characteristics, psychological questionnaires to blood proteomics. Outcome measures after incision were pain intensity ratings and the extent of the area of hyperalgesia to mechanical stimuli surrounding the incision as a proxy of central sensitization. A multi-step logistic regression analysis was performed to predict outcome measures based on feature combinations using data-driven cross-validation and prognostic model development. Phenotype-based stratification resulted in the identification of low and high responders for both outcome measures. Regression analysis revealed prognostic proteomic, specific psychophysical and psychological parameters. A combinatorial set of distinct parameters enabled us to predict outcome measures with increased accuracy compared to using single features. Remarkably, in high responders, protein network analysis suggested a protein signature characteristic for low-grade inflammation. Alongside, in silico drug repurposing highlighted potential treatment options employing antidiabetic and anti-inflammatory drugs. Taken together, we present here an integrated pipeline that harnesses bio-psycho-physiological data for prognostic prediction in a translational approach. This pipeline opens new avenues for clinical application with the goal tostratify patients and identify potential new targets as well as mechanistic correlates for postsurgical pain. GERMAN CLINICAL TRIALS REGISTRY: (DRKS-ID: DRKS00016641).

The cerebellum is activated by noxious stimuli and pathological pain but its role in noxious information processing remains unknown. Here, we show that in mice, cutaneous noxious electrical stimuli induced noradrenaline (NA) release from locus coeruleus (LC) terminals in the cerebellar cortex. Bergmann glia (BG) accumulated these LC-NA signals by increasing intracellular calcium in an integrative manner (‘flares’). BG flares were also elicited in response to an intraplantar capsaicin injection. Chemogenetic inactivation of LC terminals or BG in the cerebellar cortex or BG-specific knockdown of α-adrenergic receptors suppressed BG flares, reduced nocifensive licking and had analgesic effects in nerve injury-induced chronic neuropathic pain. Moreover, chemogenetic activation of BG or an intraplantar capsaicin injection reduced Purkinje cell firing, which may disinhibit the output activity of the deep cerebellar nuclei. These results suggest a role for BG in computing noxious information from the LC and in modulating pain-related behaviors by regulating cerebellar output.

The lateral parabrachial nucleus (PBN) is critically involved in neuropathic pain modulation. However, the cellular and molecular mechanisms underlying this process remain largely unknown. Here, we report that in mice, the right-sided, but not the left-sided, PBN plays an essential role in the development of hyperalgesia following nerve injury, irrespective of the injury side. Spino-parabrachial pathways targeting the right-sided PBN display short-term facilitation, and right-sided PBN neurons exhibit an increase in the excitability and activity after nerve injury. Inhibiting Tacr1-positive neurons, blocking Tacr1-encoding tachykinin 1 receptor (NK1R), or knocking down the Tacr1 gene in the right-sided, rather than left-sided, PBN alleviates neuropathic pain-induced sensory hypersensitivity. Additionally, the right-sided PBN plays a critical role in the development of hyperalgesia during the early phase of neuropathic pain. These results highlight the essential role of NK1R in the lateralized modulation of neuropathic pain by the PBN, providing new insights into the mechanisms underlying neuropathic pain.

Pain is a sensory and emotional experience. How did Pat Wall, founding editor of the journal PAIN and recognized pain guru, view the relation between the brain and the experience of pain? He was certain what it is not. It is not impulses in peripheral nociceptors that light up neurons in a central pain nucleus. Rather, it is a complex “signature” of brain activity normally driven by sensory stimuli, but in the event of pathology also from ectopic sources in injured nerves and associated dorsal root ganglia. Pain signatures are modulated in many ways: suppressed by gate control and descending brain pathways, augmented by peripheral and central sensitization, and massaged by abundant central feedback and feedforward loops. Pain experience is a complex function of a conscious brain. Ultimately, to understand pain is to understand conscious perception.

Inflammation is associated with localized acidosis, however, attributing physiological and pathological roles to proton-sensitive receptors is challenging due to their diversity and widespread expression. Here, agonists of the proton-sensing GPCR, GPR65, were systematically characterized. The synthetic agonist BTB09089 (BTB) recapitulated many proton-induced signaling events and demonstrated selectivity for GPR65. BTB was used to show that GPR65 activation on fibroblast-like synoviocytes (FLS), cells that line synovial joints, results in the secretion of proinflammatory mediators capable of recruiting immune cells and sensitizing sensory neurons. Intra-articular injection of BTB resulted in GPR65-dependent sensitization of knee-innervating neurons and nocifensive behaviors in mice. Stimulation of GPR65 on human FLS also triggered the release of inflammatory mediators and synovial fluid samples from human osteoarthritis patients were shown to activate GPR65. These results suggest a role of GPR65 in mediating cell-cell interactions that drive inflammatory joint pain in both mice and humans.

Recent work demonstrates that epidermal keratinocytes are critical for normal touch sensation. However, it is unknown whether keratinocytes contribute to touch-evoked pain and hypersensitivity after tissue injury. Here, we used a mouse model of paclitaxel treatment to determine the extent to which keratinocyte activity contributes to the severe neuropathic pain that accompanies chemotherapy. We found that keratinocyte inhibition by either optogenetic or chemogenetic methods largely alleviated paclitaxel-induced mechanical hypersensitivity across acute and persistent time points from 2 days through 3 weeks. Furthermore, we found that paclitaxel exposure sensitized mouse and human keratinocytes to mechanical stimulation and enhanced currents of PIEZO1, a mechanosensitive channel highly expressed in keratinocytes. Deletion of PIEZO1 from keratinocytes alleviated paclitaxel-induced mechanical hypersensitivity in mice. These findings suggest that nonneuronal cutaneous cells contribute substantially to neuropathic pain and pave the way for the development of new pain relief strategies that target epidermal keratinocytes and PIEZO1.

Itch serves as a self-protection mechanism against harmful external agents, whereas uncontrolled and persistent itch severely influences the quality of life of patients and aggravates their diseases. Unfortunately, the existing treatments are largely ineffective. The current difficulty in treatment may be closely related to the fact that the central neural mechanisms underlying itch processing, especially descending inhibition of itch, are poorly understood. Here, we demonstrate that an excitatory descending neural circuit from rostral anterior cingulate cortex pyramidal (rACC) neurons to periaqueductal gray GABAergic (PAG) neurons plays a key role in the inhibition of itch. The activity of itch-tagged rACC neurons decreases during the itch-evoked scratching period. Artificial activation or inhibition of the neural circuits significantly impairs or enhances itch processing, respectively. Thus, an excitatory neural circuit is identified as playing a crucial inhibitory role in descending regulation of itch, suggesting that it could be a potential target for treating itch.

Mast cells are regarded as effectors in immune defense against parasites and venoms and play an essential role in the pathology of allergic diseases. More recently, mast cells have been shown to receive stimuli derived from type 2 immunity, tissue damage, stress, and inflammation. Mast cells then rapidly convert these diverse signals into appropriate, organ-specific protective reflexes that can limit inflammation or reduce tissue damage. In this review, we consider functions of mast cells in sensations-such as pain, itch, and nausea-arising from tissue insults and inflammation and the ensuing protective responses. In light of emerging data highlighting the involvement of mast cells in neuroimmune communication, we also propose that mast cells are “signal converters” linking immunological and tissue states with nervous system responses.

Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences.