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CD4 + CD25 + Foxp3 + regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, whether Treg cells hamper pain at steady state and by which mechanism is still unclear. From a meta-analysis of the transcriptomes of murine Treg and conventional T cells (Tconv), we observe that the proenkephalin gene ( Penk ), encoding the precursor of analgesic opioid peptides, ranks among the top 25 genes most enriched in Treg cells. We then present various evidence suggesting that Penk is regulated in part by members of the Tumor Necrosis Factor Receptor (TNFR) family and the transcription factor Basic leucine zipper transcription faatf-like (BATF). Using mice in which the promoter activity of Penk can be tracked with a fluorescent reporter, we also show that Penk expression is mostly detected in Treg and activated Tconv in non-inflammatory conditions in the colon and skin. Functionally, Treg cells proficient or deficient for Penk suppress equally well the proliferation of effector T cells in vitro and autoimmune colitis in vivo. In contrast, inducible ablation of Penk in Treg leads to heat hyperalgesia in both male and female mice. Overall, our results indicate that Treg might play a key role at modulating basal somatic sensitivity in mice through the production of analgesic opioid peptides., Competing Interests: NA, MP, JN, JS, AA, WL, MF, LC, MN, AC, MD, NB, GD, CP, GM No competing interests declared, (© 2024, Aubert et al.)

Conflicting evidence exists concerning the effects of nutrient intake in osteoarthritis (OA). A systematic literature review and meta-analysis were performed using PubMed, EMBASE, and Cochrane Library up to November 2021 to assess the effects of nutrients on pain, stiffness, function, quality of life, and inflammation markers. We obtained 52 references including 50 on knee OA. Twelve studies compared 724 curcumin patients and 714 controls. Using the standardized mean difference, improvement was significant with regard to pain and function in the curcumin group compared to placebo, but not with active treatment (i.e., nonsteroidal anti-inflammatory drugs, chondroitin, or paracetamol). Three studies assessed the effects of ginger on OA symptoms in 166 patients compared to 164 placebo controls. Pain was the only clinical parameter that significantly decreased. Vitamin D supplementation caused a significant decrease in pain and function. Omega-3 and vitamin E caused no changes in OA parameters. Herbal formulations effects were significant only for stiffness compared to placebo, but not with active treatment. A significant decrease in inflammatory markers was found, especially with ginger. Thus, curcumin and ginger supplementation can have a favorable impact on knee OA symptoms. Other studies are needed to better assess the effects of omega-3 and vitamin D.

The spinal dorsal horn is a major site for the induction and maintenance of mechanical allodynia, but the circuitry that underlies this clinically important form of pain remains unclear. The studies presented here provide strong evidence that the neural circuits conveying mechanical allodynia in the dorsal horn differ by the nature of the injury. Calretinin (CR) neurons in lamina II inner convey mechanical allodynia induced by inflammatory injuries, while protein kinase C gamma (PKCγ) neurons at the lamina II/III border convey mechanical allodynia induced by neuropathic injuries. Cholecystokinin (CCK) neurons located deeper within the dorsal horn (laminae III-IV) are important for both types of injuries. Interestingly, the Maf + subset of CCK neurons is composed of transient vesicular glutamate transporter 3 (tVGLUT3) neurons, which convey primarily dynamic allodynia. Identification of an etiology-based circuitry for mechanical allodynia in the dorsal horn has important implications for the mechanistic and clinical understanding of this condition., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The dorsal horns of the spinal cord and the trigeminal nuclei in the brainstem contain neuron populations that are critical to process sensory information. Neurons in these areas are highly heterogeneous in their morphology, molecular phenotype and intrinsic properties, making it difficult to identify functionally distinct cell populations, and to determine how these are engaged in pathophysiological conditions. There is a growing consensus concerning the classification of neuron populations, based on transcriptomic and transductomic analyses of the dorsal horn. These approaches have led to the discovery of several molecularly defined cell types that have been implicated in cutaneous mechanical allodynia, a highly prevalent and difficult-to-treat symptom of chronic pain, in which touch becomes painful. The main objective of this review is to provide a contemporary view of dorsal horn neuronal populations, and describe recent advances in our understanding of on how they participate in cutaneous mechanical allodynia.

The mammalian nervous system encodes many different forms of pain, from those that arise as a result of short-term low-grade interactions with noxious thermal, chemical, or mechanical sources to more serious forms of pain induced by trauma and disease. In this Review, we highlight recent advances in our understanding of the neural circuits that encode these types of pain. Promising therapeutic strategies based on recent advances are also highlighted., (Copyright © 2016, American Association for the Advancement of Science.)

Background: Tissue injury enhances pain sensitivity both at the site of tissue damage and in surrounding uninjured skin (secondary hyperalgesia). Secondary hyperalgesia encompasses several pain symptoms including pain to innocuous punctate stimuli or static mechanical allodynia. How injury-induced barrage from C-fiber nociceptors produces secondary static mechanical allodynia has not been elucidated., Methods: Combining behavioral, immunohistochemical, and Western blot analysis, the authors investigated the cell and molecular mechanisms underlying the secondary static mechanical allodynia in the rat medullary dorsal horn (MDH) using the capsaicin model (n = 4 to 5 per group)., Results: Intradermal injection of capsaicin (25 μg) into the vibrissa pad produces a spontaneous pain and a secondary static mechanical allodynia. This allodynia is associated with the activation of a neuronal network encompassing lamina I-outer lamina III, including interneurons expressing the γ isoform of protein kinase C (PKCγ) within inner lamina II (IIi) of MDH. PKCγ is concomitantly phosphorylated (+351.4 ± 79.2%, mean ± SD; P = 0.0003). Mechanical allodynia and innocuous punctate stimulus-evoked laminae I to III neuronal activation can be replicated after intracisternally applied γ-aminobutyric acid receptor type A (GABAA) antagonist (bicuculline: 0.05 μg) or reactive oxygen species (ROS) donor (tert-butyl hydroperoxide: 50 to 250 ng). Conversely, intracisternal PKCγ antagonist, GABAA receptor agonist, or ROS scavenger prevent capsaicin-induced static mechanical allodynia and neuronal activation., Conclusions: Sensitization of lamina IIi PKCγ interneurons is required for the manifestation of secondary static mechanical allodynia but not for spontaneous pain. Such sensitization is driven by ROS and GABAAergic disinhibition. ROS released during intense C-fiber nociceptor activation might produce a GABAAergic disinhibition of PKCγ interneurons. Innocuous punctate inputs carried by Aδ low-threshold mechanoreceptors onto PKCγ interneurons can then gain access to the pain transmission circuitry of superficial MDH, producing pain.

Persistent mechanical hypersensitivity that occurs in the setting of injury or disease remains a major clinical problem largely because the underlying neural circuitry is still not known. Here we report the functional identification of key components of the elusive dorsal horn circuit for mechanical allodynia. We show that the transient expression of VGLUT3 by a discrete population of neurons in the deep dorsal horn is required for mechanical pain and that activation of the cells in the adult conveys mechanical hypersensitivity. The cells, which receive direct low threshold input, point to a novel location for circuit initiation. Subsequent analysis of c-Fos reveals the circuit extends dorsally to nociceptive lamina I projection neurons, and includes lamina II calretinin neurons, which we show also convey mechanical allodynia. Lastly, using inflammatory and neuropathic pain models, we show that multiple microcircuits in the dorsal horn encode this form of pain., (Copyright © 2015 Elsevier Inc. All rights reserved.)