Neuronal C-Reactive Protein/FcγRI Positive Feedback Proinflammatory Signaling Contributes to Nerve Injury Induced Neuropathic Pain.

Neuropathic pain is difficult to treat in clinical practice, and the underlying mechanisms are insufficiently elucidated. Previous studies have demonstrated that the neuronal Fc-gamma-receptor type I (FcγRI) of the dorsal root ganglion (DRG) mediates antigen-specific pain. However, the mechanisms of neuronal FcγRI in neuropathic pain remain to be explored. Here, it is found that the activation of FcγRI-related signals in primary neurons induces neuropathic pain in a rat model. This work first reveals that sciatic nerve injury persistently activates neuronal FcγRI-related signaling in the DRG, and conditional knockout (CKO) of the FcγRI-encoding gene Fcgr1 in rat DRG neurons significantly alleviates neuropathic pain after nerve injury. C-reactive protein (CRP) is increased in the DRG after nerve injury, and CRP protein of the DRG evokes pain by activating neuronal FcγRI-related signals. Furthermore, microinjection of naive IgG into the DRG alleviates neuropathic pain by suppressing the activation of neuronal FcγRI. These results indicate that the activation of neuronal CRP/FcγRI-related signaling plays an important role in the development of neuropathic pain in chronic constriction injury (CCI) rats. The findings may provide novel insights into the neuroimmune responses after peripheral nerve injury and suggest potential therapeutic targets for neuropathic pain.

Phosphorylation-dependent positive feedback on the oxytocin receptor through the kinase PKD1 contributes to long-term social memory.

Social memory enables one to recognize and distinguish specific individuals. It is fundamental to social behaviors that can be mediated by the oxytocin receptor (OXTR), such as forming relationships. We investigated the molecular regulation and function of OXTR in animal behavior involving social memory. We found that Ser261 in OXTR was phosphorylated by protein kinase D1 (PKD1). Neuronal Ca2+ signaling and behavior analyses revealed that rats expressing a mutated form of OXTR that cannot be phosphorylated at this residue (OXTR S261A) in the medial amygdala (MeA) exhibited impaired long-term social memory (LTSM). Blocking the phosphorylation of wild-type OXTR in the MeA using an interfering peptide in rats or through conditional knockout of Pkd1 in mice reduced social memory retention, whereas expression of a phosphomimetic mutant of OXTR rescued it. In HEK293A cells, the PKD1-mediated phosphorylation of OXTR promoted its binding to Gq protein and, in turn, OXTR-mediated phosphorylation of PKD1, indicating a positive feedback loop. In addition, OXTR with a single-nucleotide polymorphism found in humans (rs200362197), which has a mutation in the conserved recognition region in the PKD1 phosphorylation site, showed impaired activation and signaling in vitro and in HEK293A cells similar to that of the S216A mutant. Our findings describe a phosphoregulatory loop for OXTR and its critical role in social behavior that might be further explored in associated disorders.

Failure of Placebo Analgesia Model in Rats with Inflammatory Pain.

With the shifting role of placebos, there is a need to develop animal models of placebo analgesia and elucidate the mechanisms underlying the effect. In the present study, male Sprague-Dawley rats with chronic inflammatory pain caused by complete Freund's adjuvant (CFA) underwent a series of conditioning procedures, in which morphine was associated with different cues, but they failed to induce placebo analgesia. Then, conditioning with the conditioned place preference apparatus successfully induced analgesic expectancy and placebo analgesia in naïve rats but only induced analgesic expectancy and no analgesic effect in CFA rats. Subsequently, we found enhanced c-fos expression in the nucleus accumbens and reduced expression in the anterior cingulate cortex in naïve rats while c-fos expression in the anterior cingulate cortex in CFA rats was not altered. In summary, the behavioral conditioning model demonstrated the difficulty of establishing a placebo analgesia model in rats with a pathological condition.