Genetics

Molecular Pathophysiology of Pain Resolution

The molecular pathophysiology of chronic pain states is largely unknown. The genetic and molecular studies of pain in both humans and mice nevertheless can provide critical insights into pathophysiological mechanisms of pain chronification. Increasing evidence suggests that resolution of actue pain requires an active molecular process and production of specilized pro-resolving mediators (SPMs). Failure in this resolution process will cause chronin pain. In this session, we will discuss the crucial importance of pain resolution processes and re-emphasize the perhaps counterintuitive concept that an active biological process underlies pain resolution rather than pain progression to chronic status. Our results suggest that this process is impaired in those who do not resolve acute pain over time and suggest time stratification of a cascade of processes resulting in a return to a normal, no-pain state. Dr. Diatchenko will illustrate this concept using blood samples of patients with acute low back pain. Dr. Ji will discuss the role of SPMs and their receptors in resolving inflammatory and neuropathic pain in animals via neuro-immune interactions. Dr. Malcangio will discuss how interactions between chemokine and SPM receptors control the phenotype of immune cells in the resolution of inflammatory arthritis pain.

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Acute Inflammatory Response via Neutrophil Activation Protects Against Pain Chronification

The transition of acute to chronic pain represents a critical point of medical intervention. Here, I will report the investigation of the pathophysiological mechanisms underlying the transition from acute to chronic low back pain (LBP) at the transcriptome-wide level in peripheral immune cells. Transcriptomic changes were compared between patients whose LBP was resolved at three months with those whose LBP persisted. Hypotheses emerging from the transcriptomic analyses were addressed using mouse models and a large population sample. We found thousands of dynamic transcriptional changes over three months in LBP participants with resolved pain but none in those with persistent pain, such that transient neutrophil-driven upregulation of inflammatory responses was protective against pain chronification. In mouse pain assays, early treatment with a steroidal or non-steroidal anti-inflammatory drug (NSAID) also led to prolonged pain despite being analgesic short term; such a prolongation was not observed with other analgesics. Depletion of neutrophils greatly delayed resolution of pain in mice while peripheral injection of neutrophils themselves prevented the development of long-lasting pain induced by an anti-inflammatory drug. Analysis of pain trajectories of human subjects reporting acute back pain in UK Biobank identified elevated risk of pain persistence for those taking NSAIDs.

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Neuroprotectin D1 and GPR37 in the Resolution of Pathological Pain via Neuroimmune Regulation

Increasing evidence suggests that resolution of acute pain requires an active molecular process and production of specialized pro-resolving mediators (SPMs), including resolvins, protectins, maresins, and lipoxins. Protectin D1/neuroprotectin D1 (PD1/NPD1) is a SPM derived from fish oil DHA and possess potent anti-inflammatory and pro-resolution actions in animal models. NPD1 produces potent pain relief in animal models of inflammatory, neuropathic, and cancer pain. We recently identified GPR37 as a novel receptor for NPD1. GPR37 is expressed by macrophages, DRG neurons, and spinal cord oligodendrocytes. Notably, Gpr37 knockout mice show deficits in resolving inflammatory pain and infection-induced pain. GPR37 regulates the resolution of pathological pain by altering macrophage M1/M2 phenotype and promoting macrophage phagocytosis. NPD1 also promotes axonal outgrowh in DRG neurons. Furthermore, GPR37 agonists control inflammation and protect against septic death in animal models of infections. Together, these findings suggest that the NPD1/GPR37 axis regulates the resolution of pain and inflammation via both neuronal and non-neuronal regulations. Finally, I will highlight “resolution pharmacology” for the resolution of pain.

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Chemokines and Lipid Mediators Modulate the Resolution of Inflammatory Arthritis Pain

Pain is a persistent feature of rheumatoid arthritis and sensory neuron-macrophage crosstalk in the dorsal root ganglia (DRG) plays a fundamental role for the establishment and maintenance of RA pain. In the K/BxN serum-transfer model of inflammatory arthritis, we observed that hind paw hypersensitivity (allodynia) persists after joint swelling is resolved. This phase is associated with the presence of CX3CR1-macrophages into the DRG and an imbalance in lipid mediators. Specifically, we found no difference in prostaglandins PGD2 and PGE2 levels, but a significant decrease in the pro-resolving lipid mediator Maresin1 (MaR1). The administration of MaR1 reversed K/BxN serum-transfer allodynia and this effect was maintained for 2 weeks after the last administration. Analysis of leukocytes in the DRG revealed that MaR1 treatment was associated with lower numbers of pro-inflammatory macrophages. Altogether these observations suggest that MaR1 treatment attenuates allodynia in inflammatory arthritis and reduces macrophage infiltration. I will discuss the proposal that inflammatory pain and pain that persists when inflammation is resolving may be reliant on partially distinct mechanisms, both involving monocytes/macrophages and biosynthesis of lipid mediators. CX3CR1-mediated mechanisms and lipid mediator biosynthesis facilitate such crosstalk and may constitute novel targets for the resolution of RA pain.

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