Sensory nerves directly promote osteoclastogenesis by secreting Cyp40

BackgroundGiven the afferent functions, sensors have been found exerting efferent influences and directly alter organ physiology. Sensory nerves have been found critical in osteoclasts and bone resorption. However, the direct evidence of whether sensory nerve efferent influences osteoclast, remains lacking. MethodsWe treated mice with resiniferatoxin (RTX) or complete Freund’s adjuvant (CFA) to induce sensory hypersensitivity. Bone histomorphometry including micro-ct, three-point bending assay, von kossa staining, calcein double labeling, toluidine blue staining, and trap staining were performed to monitor bone quality and bone cells. Multiple virus vectors were applied to trace signals between sensory nerves and osteoclasts. Sensory neurons (SN) and osteoclasts were cocultured to study the effects and mechanisms of the sensory nerves on osteoclasts in vitro. Isobaric tag for relative and absolute quantitation (iTRAQ) was used to identify secreted proteins in the sensory nerve. ResultsHere, we found sensory hypersensitivity significantly increased osteoclast bone resorption; SN directly promote osteoclastogenesis in vitro; and abundant sensory efferent signals transported into osteoclasts. Then our screening identified a novel neuropeptide Peptidyl-prolyl cis-trans isomerase D (Cyp40), is the reverse signal from the sensory nerve and plays a critical role for osteoclastogenesis, via aryl hydrocarbon receptor (AhR)-Ras/Raf-pErk-NFATc1 pathway. The efferent signals from sensory nerves tend to involves in the rapid feedback process: vast majority of sensory efferent signals (87.28%) present in fast-twitch myofibers. ConclusionThis study revealed a novel mechanism of sensory nerves on osteoclasts: the direct promotion of osteoclastogenesis by the Cyp40. This mechanism may represent a direct, and quick response of sensory nerves to the changes in bone. Targeting the Cyp40 could therefore be a strategy to promote bone repair at the early stage of bone injury.

Auditory Hypersensitivity and Processing Deficits in a Rat Model of Fragile X Syndrome

Fragile X (FX) syndrome is one of the leading inherited causes of autism spectrum disorder (ASD). A majority of FX and ASD patients exhibit sensory hypersensitivity, including auditory hypersensitivity or hyperacusis, a condition in which everyday sounds are perceived as much louder than normal. Auditory processing deficits in FX and ASD also afford the opportunity to develop objective and quantifiable outcome measures that are likely to translate between humans and animal models due to the well-conserved nature of the auditory system and well-developed behavioral read-outs of sound perception. Therefore, in this study we characterized auditory hypersensitivity in a Fmr1 knockout (KO) transgenic rat model of FX using an operant conditioning task to assess sound detection thresholds and suprathreshold auditory reaction time-intensity (RT-I) functions, a reliable psychoacoustic measure of loudness growth, at a variety of stimulus frequencies, bandwidths and durations. Male Fmr1 KO and littermate WT rats both learned the task at the same rate and exhibited normal hearing thresholds. However, Fmr1 KO rats had faster auditory RTs over a broad range of intensities and steeper RT-I slopes than WT controls, perceptual evidence of excessive loudness growth in Fmr1 KO rats. Furthermore, we found that Fmr1 KO animals exhibited abnormal perceptual integration of sound duration and bandwidth, with diminished temporal but enhanced spectral integration of sound intensity. Because temporal and spectral integration of sound stimuli were altered in opposite directions in Fmr1 KO rats, this suggests that abnormal RTs in these animals are evidence of aberrant auditory processing rather than generalized hyperactivity or altered motor responses. Together, these results are indicative of fundamental changes to low-level auditory processing in Fmr1 KO animals. Finally, we demonstrated that antagonism of metabotropic glutamate receptor 5 (mGlu5) selectively and dose-dependently restored normal loudness growth in Fmr1 KO rats, suggesting a pharmacologic approach for alleviating sensory hypersensitivity associated with FX. This study leverages the tractable nature of the auditory system and the unique behavioral advantages of rats to provide important insights into the nature of a centrally important yet understudied aspect of FX and ASD.

Investigating the relationships between the burden of multiple sensory hypersensitivity symptoms and headache-related disability in patents with migraine

Objective Sensory hypersensitivities such as photophobia, phonophobia, and osmophobia are common in patients with migraine. We investigated the burden of these multiple sensory hypersensitivities in migraine. Methods In this cross-sectional study, 187 consecutive patients with migraine (26 men/161 women; age, 45.9 ± 13.2 years) were included. Sensory hypersensitivity symptoms such as photo−/phono−/osmophobia and accompanying symptoms were determined by neurologists in interviews. The Migraine Disability Assessment (MIDAS) was used to assess headache-related disability. The Kessler Psychological Distress Scale (K6) was also administered. Results Photophobia, phonophobia and osmophobia were observed in 75.4%, 76.5% and 55.1% of the patients with migraine, respectively. A significant overlap in sensory hypersensitivities (photo−/phono−/osmophobia) was found; the proportions of patients with 2 and 3 coexisting sensory hypersensitivities were 33.2% and 41.7%, respectively. The MIDAS score was higher in those with 3 sensory hypersensitivity symptoms than in those with 0 to 2 sensory hypersensitivity symptoms. A generalized linear model with ordinal logistic regression analysis revealed that multiple sensory hypersensitivities, younger age, more migraine days per month, and a higher K6 score were significantly related to the higher MIDAS score. Conclusion Our study showed that sensory hypersensitivities commonly occur and overlap in patients with migraine and that multiple sensory hypersensitivity symptoms have a significant impact on headache-related disability.

Oxaliplatin Depolarizes the IB4– Dorsal Root Ganglion Neurons to Drive the Development of Neuropathic Pain Through TRPM8 in Mice

Use of chemotherapy drug oxaliplatin is associated with painful peripheral neuropathy that is exacerbated by cold. Remodeling of ion channels including TRP channels in dorsal root ganglion (DRG) neurons contribute to the sensory hypersensitivity following oxaliplatin treatment in animal models. However, it has not been studied if TRP channels and membrane depolarization of DRG neurons serve as the initial ionic/membrane drives (such as within an hour) that contribute to the development of oxaliplatin-induced neuropathic pain. In the current study, we studied in mice (1) in vitro acute effects of oxaliplatin on the membrane excitability of IB4+ and IB4– subpopulations of DRG neurons using a perforated patch clamping, (2) the preventative effects of a membrane-hyperpolarizing drug retigabine on oxaliplatin-induced sensory hypersensitivity, and (3) the preventative effects of TRP channel antagonists on the oxaliplatin-induced membrane hyperexcitability and sensory hypersensitivity. We found (1) IB4+ and IB4– subpopulations of small DRG neurons displayed previously undiscovered, substantially different membrane excitability, (2) oxaliplatin selectively depolarized IB4– DRG neurons, (3) pretreatment of retigabine largely prevented oxaliplatin-induced sensory hypersensitivity, (4) antagonists of TRPA1 and TRPM8 channels prevented oxaliplatin-induced membrane depolarization, and (5) the antagonist of TRPM8 largely prevented oxaliplatin-induced sensory hypersensitivity. These results suggest that oxaliplatin depolarizes IB4– neurons through TRPM8 channels to drive the development of neuropathic pain and targeting the initial drives of TRPM8 and/or membrane depolarization may prevent oxaliplatin-induce neuropathic pain.

Photophobia and allodynia in persistent post-traumatic headache are associated with higher disease burden

Objective To assess photophobia and allodynia in subjects with post-traumatic headache and examine how these sensory hypersensitivities associate with clinical measures of disease burden. Background Post-traumatic headache is the most frequent and disabling long-term consequence of mild traumatic brain injury. There is evidence of sensory dysfunction in acute post-traumatic headache, and it is known from other headache conditions that sensory amplifications correlate with more severe disease. However, systematic studies in post-traumatic headache are surprisingly scarce. Methods We tested light and tactile sensitivity, along with measures of disease burden, in 30 persistent post-traumatic headache subjects and 35 controls. Results In all, 79% of post-traumatic headache subjects exhibited sensory hypersensitivity based on psychophysical assessment. Of those exhibiting hypersensitivity, 54% exhibited both light and tactile sensitivity. Finally, sensory thresholds were correlated across modalities, as well as with headache attack frequency. Conclusions In this study, post-traumatic headache subjects with both light and tactile sensitivity had significantly higher headache frequencies and lower sensitivity thresholds to both modalities, compared to those with single or no sensory hypersensitivity. This pattern suggests that hypersensitivity across multiple modalities may be functionally synergistic, reflect a higher disease burden, and may serve as candidate markers of disease.

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats

The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemogenetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats

The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemo-genetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.