Function and postnatal changes of dural afferent fibers expressing TRPM8 channels

BACKGROUND: Genome-wide association studies have identified TRPM8 (transient receptor potential melastatin 8) as one of the susceptibility genes for common migraine. Here, we investigated the postnatal changes of TRPM8-expressing dural afferent fibers as well as the function of dural TRPM8 channels in mice. RESULTS: First, we quantified the density and the number of axonal branches of TRPM8-expressing fibers in the dura of mice expressing farnesylated enhanced green fluorescent protein (EGFPf) from one TRPM8 allele between postnatal day 2 (P2) to adulthood. The number of axonal branches on individual dural EGFP-positive fibers was decreased by 30% between P2 and P11. The density of dural EGFP-positive fibers was subsequently reduced by 50% between P16 and P21. Conversely, the density and the number of branches of axons expressing calcitonin gene-related peptide remained stable in postnatal mouse dura. The density of TRPM8-expressing fibers innervating the mouse cornea epithelium was significantly increased from P2 to adulthood. Next, we tested the function of dural TRPM8 channels in adult mice and found that TRPM8 agonist menthol effectively inhibited the nocifensive behavior evoked by dural application of inflammatory mediators. CONCLUSIONS: Our results indicate that the TRPM8-expressing dural afferent fibers undergo cell- and target tissue-specific axonal pruning during postnatal development. Activation of dural TRPM8 channels decreases meningeal irritation-evoked nocifensive behavior in adult mice. This provides a framework to further explore the role of postnatal changes of TRPM8-expressing dural afferents in the pathophysiology of pediatric and adult migraine. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12990-015-0043-0) contains supplementary material, which is available to authorized users

Correlation between the exchange bias effect and antisite disorders in Sr2−x_{2-x}Lax_xCoNbO6_6

We unravel the effect of La substitution and hence antisite disorders on the exchange bias (EB) mechanism in Sr$_{2-x}$La$_x$CoNbO$_6$ ($x=$ 0, 0.2) double perovskite samples using the detailed analysis of the field cooled magnetization isotherms (M--H) and training effect. The field dependence of the freezing temperature deviates from both Gabay-Toulouse (GT) and de Almeida-Thouless (AT) lines and the analysis suggests that the $x=$ 0 sample follows a different universality class with moderate anisotropy in the frozen spins. Interestingly, we find that the EB effect is significantly suppressed in the $x=$ 0.2 sample due to increase [decrease] in the size of ferromagnetic (FM) [cluster glass (CG)] domain, which reduces the effective disordered interface responsible for the EB. The changes in fraction of FM, AFM, and CG like interactions with the La substitution and applied magnetic field are found to be crucial in governing the EB effect in these samples. Further, the training effect measurements show the unequal shift in the left and right branches of the M--H loops and their different evolution with the field cycles ($n$). The analysis reveals that the rotatable spins relax approximately one order of magnitude faster than the frozen spins at the disordered interface. We find a possible correlation between the observed EB effect and the antisite disorders in these samples.Comment: submitte

Evidence of discrete energy states and cluster-glass behavior in Sr2−x_{2-x}Lax_xCoNbO6_6

We report the detailed analysis of specific heat [C$_{\rm P}$(T)] and ac-susceptibility for magnetically frustrated Sr$_{2-x}$La$_x$CoNbO$_6$ ($x=$ 0--1) double perovskites to understand low temperature complex magnetic interactions and their evolution with $x$. Interestingly, the observed Schottky anomaly in the $x\leqslant$ 0.4 samples shifts gradually towards higher temperature with magnetic field as well as $x$, and the analysis reveal the persistence of the discrete energy states in these samples resulting from the spin-orbit coupling and octahedral distortion. Moreover, the extracted values of Land\'e g--factor indicate the existence of high-spin state Co$^{3+}$ ions close to non-magnetic low-spin state. The specific heat data show the $\lambda$-type anomaly for the $x\geqslant$ 0.6 samples due to evolution of the long range antiferromagnetic ordering. Our analysis of low temperature C$_{\rm P}$(T) data for the $x\geqslant$ 0.6 samples demonstrate the 3D isotropic Heisenberg antiferromagnetic (AFM) interactions and the temperature induced second order AFM--paramagnetic phase transition. More interestingly, we demonstrate the presence of the free Co$^{2+}$ like Kramers doublet ground state in the $x =$1 sample. Further, the ac susceptibility and time evolution of the magnetization data reveal the low temperature cluster-glass like behavior in the $x=$ 0--0.4 samples, where spin-spin correlation strength decreases with $x$.Comment: accepted for publication in PR

Probing the electronic and local structure of Sr2−x_{2-x}Lax_xCoNbO6_6 using near-edge and extended x-ray absorption fine structures

We report the electronic and local structural investigation of double pervoskites Sr$_{2-x}$La$_x$CoNbO$_6$ ($x=$ 0--1) using x-ray absorption near edge structure (XANES) and extended x-ray absorption fine structures (EXAFS) at the Nb, Co, and Sr $K$-edges. The $ab$ $initio$ simulations and detailed analysis of the Nb and Co $K$-edge XANES spectra demonstrate that the observed pre-edge features arise from the transition of 1$s$ electrons to the mixed $p-d$ hybridized states. We reveal a $z$-out Jahn-Teller (JT) distortion in the CoO$_6$ octahedra, which decreases monotonically due to an enhancement in the JT inactive Co$^{2+}$ ions with $x$ . On the other hand, the $z$-in distortion in NbO$_6$ octahedra remains unaltered up to $x=$ 0.4 and then decreases with further increase in $x$. This sudden change in the local coordination around Nb atoms is found to be responsible for the evolution of the antiferromagnetic interactions in $x \geqslant$ 0.6 samples. Also, we establish a correlation between the degree of octahedral distortion and intensity of the white line feature in the XANES spectra and possible reason for this are discussed. More interestingly, we observe the signature of KN$_1$ double electron excitation in the Sr $K$-edge EXAFS spectra for all the samples, which is found to be in good agreement with the $Z$+1 approximation. Further, the Co L$_{2,3}$ edge shows the reduction in the crystal field strength and hence an increase in the charge transfer energy ($\Delta_{ct}$) with the La substitution.Comment: submitte

Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1

<p>Abstract</p> <p>Background</p> <p>A number of prostaglandins (PGs) sensitize dorsal root ganglion (DRG) neurons and contribute to inflammatory hyperalgesia by signaling through specific G protein-coupled receptors (GPCRs). One mechanism whereby PGs sensitize these neurons is through modulation of "thermoTRPs," a subset of ion channels activated by temperature belonging to the Transient Receptor Potential ion channel superfamily. Acrid, electrophilic chemicals including cinnamaldehyde (CA) and allyl isothiocyanate (AITC), derivatives of cinnamon and mustard oil respectively, activate thermoTRP member TRPA1 via direct modification of channel cysteine residues.</p> <p>Results</p> <p>Our search for endogenous chemical activators utilizing a bioactive lipid library screen identified a cyclopentane PGD₂metabolite, 15-deoxy-Δ^12,14-prostaglandin J₂(15d-PGJ₂), as a TRPA1 agonist. Similar to CA and AITC, this electrophilic molecule is known to modify cysteines of cellular target proteins. Electophysiological recordings verified that 15d-PGJ₂specifically activates TRPA1 and not TRPV1 or TRPM8 (thermoTRPs also enriched in DRG). Accordingly, we identified a population of mouse DRG neurons responsive to 15d-PGJ₂and AITC that is absent in cultures derived from TRPA1 knockout mice. The irritant molecules that activate TRPA1 evoke nociceptive responses. However, 15d-PGJ₂has not been correlated with painful sensations; rather, it is considered to mediate anti-inflammatory processes via binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ). Our <it>in vivo </it>studies revealed that 15d-PGJ₂induced acute nociceptive responses when administered cutaneously. Moreover, mice deficient in the TRPA1 channel failed to exhibit such behaviors.</p> <p>Conclusion</p> <p>In conclusion, we show that 15d-PGJ₂induces acute nociception when administered cutaneously and does so via a TRPA1-specific mechanism.</p