Accepted

Pain is a complex, multidimensional experience that involves dynamic interactions between sensory-discriminative and affective-emotional processes. Pain experiences have a high degree of variability depending on their context and prior anticipation. Viewing pain perception as a perceptual inference problem, we propose a predictive coding paradigm to characterize evoked and non-evoked pain. We record the local field potentials (LFPs) from the primary somatosensory cortex (S1) and the anterior cingulate cortex (ACC) of freely behaving rats-two regions known to encode the sensory-discriminative and affective-emotional aspects of pain, respectively. We further use predictive coding to investigate the temporal coordination of oscillatory activity between the S1 and ACC. Specifically, we develop a phenomenological predictive coding model to describe the macroscopic dynamics of bottom-up and top-down activity. Supported by recent experimental data, we also develop a biophysical neural mass model to describe the mesoscopic neural dynamics in the S1 and ACC populations, in both naive and chronic pain-treated animals. Our proposed predictive coding models not only replicate important experimental findings, but also provide new prediction about the impact of the model parameters on the physiological or behavioral read-out-thereby yielding mechanistic insight into the uncertainty of expectation, placebo or nocebo effect, and chronic pain.

Glycinergic neurons and glycine receptors (GlyRs) exert a critical control over spinal nociception. Prostaglandin E2 (PGE2), a key inflammatory mediator produced in the spinal cord in response to peripheral inflammation, inhibits a certain subtype of GlyRs (α3GlyR) that is defined by the inclusion of α3 subunits and distinctly expressed in the lamina II of the spinal dorsal horn, i.e., at the site where most nociceptive nerve fibers terminate. Previous work has shown that the hyperalgesic effect of spinal PGE2 is lost in mice lacking α3GlyRs and suggested that this phenotype results from the prevention of PGE2-evoked protein kinase A (PKA)-dependent phosphorylation and inhibition of α3GlyRs. However, direct proof for a contribution of this phosphorylation event to inflammatory hyperalgesia was still lacking. In order to address this knowledge gap, a phospho-deficient mouse line was generated that carries a serine to alanine point mutation at a strong consensus site for PKA-dependent phosphorylation in the long intracellular loop of the GlyR α3 subunit. These mice showed unaltered spinal expression of GlyR α3 subunits. In behavioral experiments, they showed no alterations in baseline nociception, but were protected from the hyperalgesic effects of intrathecally injected PGE2 and exhibited markedly reduced inflammatory hyperalgesia. These behavioral phenotypes closely recapitulate those found previously in GlyR α3-deficient mice. Our results thus firmly establish the crucial role of PKA-dependent phosphorylation of α3GlyR the inflammatory hyperalgesia.

Extracellular vesicles (EVs) are capable of transferring microRNAs (miRNAs or miRs) between two different types of cells and also serve as vehicles for delivery of therapeutic molecules. After peripheral nerve injury, abnormal expression patterns of miRNAs have been observed in dorsal root ganglia (DRG) sensory neurons. We hypothesized that sensory neurons secrete miRs-containing EVs to communicate with macrophages. We demonstrated that miR-23a was upregulated in DRG neurons in spared nerve injury (SNI) mouse models. We also found that miR-23a was enriched in EVs released by cultured DRG neurons following capsaicin treatment. miR-23a-containing EVs were taken up into macrophages in which increased intracellular miR-23a promoted pro-inflammatory phenotype. A20 was verified as a target gene of miR-23a. Moreover, intrathecal delivery of EVs-miR-23a antagomir attenuated neuropathic hypersensitivity and reduced the number of M1 macrophages in injured DRGs by targeting A20. In conclusion, these results demonstrate that sensory neurons transfer EVs-encapsulated miR-23a to activate M1 macrophages and enhance neuropathic pain following the peripheral nerve injury. The study highlighted a new therapeutic approach to alleviate chronic neuropathic pain after nerve trauma by targeting detrimental miRNA in sensory neurons.

While the prevalence of radiographic and symptomatic osteoarthritis (OA) is higher in women, male mice are more frequently used in animal experiments to explore its pathogenesis or drug efficacy. In this study, we examined whether sexual dimorphism affects pain and joint degeneration in destabilization of the medial meniscus (DMM) mouse model.

Lumbar spinal canal stenosis (LSS) or mechanical compression of dorsal root ganglion (DRG) is one of the causes of low back pain and neuropathic pain (NP). Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator that is produced mainly from lysophosphatidylcholine (LPC) via autotaxin (ATX) and is known to induce NP via LPA receptor signaling in mice. Recently, we demonstrated that LPC and LPA were higher in cerebrospinal fluid (CSF) of patients with LSS. Based on the possible potential efficacy of the ATX inhibitor for NP treatment, we used an NP model with compression of DRG (CD model) and investigated LPA dynamics and whether ATX inhibition could ameliorate NP symptoms, using an orally available ATX inhibitor (ONO-8430506) at a dose of 30 mg/kg. In CD model, we observed increased LPC and LPA levels in CSF, and decreased threshold of the pain which were ameliorated by oral administration of the ATX inhibitor with decreased microglia and astrocyte populations at the site of the spinal dorsal horn projecting from injured DRG. These results suggested possible efficacy of ATX inhibitor for the treatment of NP caused by spinal nerve root compression and involvement of the ATX-LPA axis in the mechanism of NP induction.

Pathogen infection triggers pain via activation of the innate immune system. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are the main components of innate immunity and have been implicated in pain signaling. We previously revealed that the TLR2-NLRP3-IL33 pathway mediates inflammatory pain responses during hyperactivity of innate immunity. However, their roles in neuropathic pain had remained unclear. Here we report that although knockout of TLR2 or NLRP3 does not affect spared nerve injury (SNI)-induced neuropathic pain, intrathecal inhibition of IL33/ST2 signaling with ST2 neutralizing antibodies reverses mechanical thresholds in SNI mice compared to PBS vehicle treated animals. This effect indicates a universal role of IL33 in both inflammatory and neuropathic pain states, and that targeting the IL33/ST2 axis could be a potential therapeutic approach for pain treatment.