J-2156, a small molecule somatostatin type 4 receptor agonist, alleviated hindpaw hypersensitivity in the streptozotocin-induced rat model of painful diabetic neuropathy but with a 2-fold decrease in potency at an advanced stage in the model, mimicking morphine.

There is a large unmet need for novel pain-killers to improve relief of painful diabetic neuropathy (PDN). Herein, we assessed the efficacy of the somatostatin type 4 (SST4) receptor agonist, J-2156, for relief of PDN in rats. Diabetes was induced with streptozotocin (STZ; 70 mg/kg) and bilateral hindpaw hypersensitivity was fully developed by 8-week post-STZ. In the intervals, 8-12-weeks (morphine-sensitive phase; Phase 1) and 16-18-weeks (morphine-hyposensitive phase; Phase 2) post-STZ, rats received a single dose of intraperitoneal (i.p.) J-2156 (10, 20, 30 mg/kg), gabapentin (100 mg/kg i.p.), subcutaneous morphine (1 mg/kg) or vehicle. Hindpaw withdrawal thresholds (PWTs) were assessed using von Frey filaments pre-dose and at regular intervals over 3-h post-dose. In Phase 1, J-2156 at 30 mg/kg evoked significant anti-allodynia in the hindpaws with maximal effect at 1.5 h compared with 1 h for gabapentin and morphine. The durations of action for all three compounds were greater than 3 h. The corresponding mean (±SEM) extent and duration of anti-allodynia (ΔPWT AUC) for gabapentin did not differ significantly from that for J-2156 (30 mg/kg) or morphine. However, in Phase 2, the ΔPWT AUC for morphine was reduced to approximately 25% of that in Phase 1, mirroring our previous work. Similarly, the mean (±SEM) ΔPWT AUC for J-2156 (30 mg/kg) in Phase 2 was approximately 45% of that for Phase 1 whereas for gabapentin the mean (±SEM) ΔPWT AUCs did not differ significantly (p > 0.05) between the two phases. Our findings further describe the preclinical pain relief profile of J-2156 and complement previous work in rat models of inflammatory pain, neuropathic pain and low back pain. SST4 receptor agonists hold promise as novel therapeutics for the relief of PDN, a type of peripheral neuropathic pain that is often intractable to relief with clinically used drug treatment options.

Emerging symmetric strain response and weakening nematic fluctuations in strongly hole-doped iron-based superconductors.

Electronic nematicity is often found in unconventional superconductors, suggesting its relevance for electronic pairing. In the strongly hole-doped iron-based superconductors, the symmetry channel and strength of the nematic fluctuations, as well as the possible presence of long-range nematic order, remain controversial. Here, we address these questions using transport measurements under elastic strain. By decomposing the strain response into the appropriate symmetry channels, we demonstrate the emergence of a giant in-plane symmetric contribution, associated with the growth of both strong electronic correlations and the sensitivity of these correlations to strain. We find weakened remnants of the nematic fluctuations that are present at optimal doping, but no change in the symmetry channel of nematic fluctuations with hole doping. Furthermore, we find no indication of a nematic-ordered state in the AFe2As2 (A = K, Rb, Cs) superconductors. These results revise the current understanding of nematicity in hole-doped iron-based superconductors.

Dominant In-Plane Symmetric Elastoresistance in CsFe_{2}As_{2}.

We study the elastoresistance of the highly correlated material CsFe_{2}As_{2} in all symmetry channels. Neutralizing its thermal expansion by means of a piezoelectric-based strain cell is demonstrated to be essential. The elastoresistance response in the in-plane symmetric channel is found to be large, while the response in the symmetry-breaking channels is weaker and provides no evidence for a divergent nematic susceptibility. Rather, our results can be interpreted naturally within the framework of a coherence-incoherence crossover, where the low-temperature coherent state is sensitively tuned by the in-plane atomic distances.

Ferroelasticity, anelasticity and magnetoelastic relaxation in Co-doped iron pnictide: Ba(Fe0.957Co0.043)2As2.

The hypothesis that strain has a permeating influence on ferroelastic, magnetic and superconducting transitions in 122 iron pnictides has been tested by investigating variations of the elastic and anelastic properties of a single crystal of Ba(Fe0.957Co0.043)2As2 by resonant ultrasound spectroscopy as a function of temperature and externally applied magnetic field. Non-linear softening and stiffening of C 66 in the stability fields of both the tetragonal and orthorhombic structures has been found to conform quantitatively to the Landau expansion for a pseudoproper ferroelastic transition which is second order in character. The only exception is that the transition occurs at a temperature (T S ≈ 69 K) ~10 K above the temperature at which C 66 would extrapolate to zero ([Formula: see text] ≈ 59 K). An absence of anomalies associated with antiferromagnetic ordering below T N ≈ 60 K implies that coupling of the magnetic order parameter with shear strain is weak. It is concluded that linear-quadratic coupling between the structural/electronic and antiferromagnetic order parameters is suppressed due to the effects of local heterogeneous strain fields arising from the substitution of Fe by Co. An acoustic loss peak at ~50-55 K is attributed to the influence of mobile ferroelastic twin walls that become pinned by a thermally activated process involving polaronic defects. Softening of C 66 by up to ~6% below the normal-superconducting transition at T c ≈ 13 K demonstrates an effective coupling of the shear strain with the order parameter for the superconducting transition which arises indirectly as a consequence of unfavourable coupling of the superconducting order parameter with the ferroelastic order parameter. Ba(Fe0.957Co0.043)2As2 is representative of 122 pnictides as forming a class of multiferroic superconductors in which elastic strain relaxations underpin almost all aspects of coupling between the structural, magnetic and superconducting order parameters and of dynamic properties of the transformation microstructures they contain.

Strain relaxation behaviour of vortices in a multiferroic superconductor.

The elastic and anelastic properties of a single crystal of Co-doped pnictide Ba(Fe0.957Co0.043)2As2 have been determined by resonant ultrasound spectroscopy in the frequency range 10-500 kHz, both as a function of temperature through the normal-superconducting transition (T c ≈ 12.5 K) and as a function of applied magnetic field up to 12.5 T. Correlation with thermal expansion, electrical resistivity, heat capacity, DC and AC magnetic data from crystals taken from the same synthetic batch has revealed the permeating influence of strain on coupling between order parameters for the ferroelastic (Q E) and superconducting (Q SC) transitions and on the freezing/relaxation behaviour of vortices. Elastic softening through T c in zero field can be understood in terms of classical coupling of the order parameter with the shear strain e 6, λe 6 [Formula: see text], which means that there must be a common strain mechanism for coupling of the form λ [Formula: see text] Q E. At fields of ~5 T and above, this softening is masked by Debye-like stiffening and acoustic loss processes due to vortex freezing. The first loss peak may be associated with the establishment of superconductivity on ferroelastic twin walls ahead of the matrix and the second is due to the vortex liquid-vortex glass transition. Strain contrast between vortex cores and the superconducting matrix will contribute significantly to interactions of vortices both with each other and with the underlying crystal structure. These interactions imply that iron-pnictides represent a class of multiferroic superconductors in which strain-mediated coupling occurs between the multiferroic properties (ferroelasticity, antiferromagnetism) and superconductivity.

Hedgehog Spin-Vortex Crystal Antiferromagnetic Quantum Criticality in CaK(Fe_{1-x}Ni_{x})_{4}As_{4} Revealed by NMR.

Two ordering states, antiferromagnetism and nematicity, have been observed in most iron-based superconductors (SCs). In contrast to those SCs, the newly discovered SC CaK(Fe_{1-x}Ni_{x})_{4}As_{4} exhibits an antiferromagnetic (AFM) state, called hedgehog spin-vortex crystal (SVC) structure, without nematic order, providing the opportunity for the investigation into the relationship between spin fluctuations and SC without any effects of nematic fluctuations. Our ^{75}As nuclear magnetic resonance studies on CaK(Fe_{1-x}Ni_{x})_{4}As_{4} (0≤x≤0.049) revealed that CaKFe_{4}As_{4} is located close to a hidden hedgehog SVC AFM quantum-critical point (QCP). The magnetic QCP without nematicity in CaK(Fe_{1-x}Ni_{x})_{4}As_{4} highlights the close connection of spin fluctuations and superconductivity in iron-based SCs. The advantage of stoichiometric composition also makes CaKFe_{4}As_{4} an ideal platform for further detailed investigation of the relationship between magnetic QCP and superconductivity in iron-based SCs without disorder effects.

Spectral Evidence for Emergent Order in Ba_{1-x}Na_{x}Fe_{2}As_{2}.

We report an angle-resolved photoemission spectroscopy study of the iron-based superconductor family, Ba_{1-x}Na_{x}Fe_{2}As_{2}. This system harbors the recently discovered double-Q magnetic order appearing in a reentrant C_{4} phase deep within the underdoped regime of the phase diagram that is otherwise dominated by the coupled nematic phase and collinear antiferromagnetic order. From a detailed temperature-dependence study, we identify the electronic response to the nematic phase in an orbital-dependent band shift that strictly follows the rotational symmetry of the lattice and disappears when the system restores C_{4} symmetry in the low temperature phase. In addition, we report the observation of a distinct electronic reconstruction that cannot be explained by the known electronic orders in the system.

Imaging orbital-selective quasiparticles in the Hund's metal state of FeSe.

Strong electronic correlations, emerging from the parent Mott insulator phase, are key to copper-based high-temperature superconductivity. By contrast, the parent phase of an iron-based high-temperature superconductor is never a correlated insulator. However, this distinction may be deceptive because Fe has five actived d orbitals while Cu has only one. In theory, such orbital multiplicity can generate a Hund's metal state, in which alignment of the Fe spins suppresses inter-orbital fluctuations, producing orbitally selective strong correlations. The spectral weights Zm of quasiparticles associated with different Fe orbitals m should then be radically different. Here we use quasiparticle scattering interference resolved by orbital content to explore these predictions in FeSe. Signatures of strong, orbitally selective differences of quasiparticle Zm appear on all detectable bands over a wide energy range. Further, the quasiparticle interference amplitudes reveal that [Formula: see text], consistent with earlier orbital-selective Cooper pairing studies. Thus, orbital-selective strong correlations dominate the parent state of iron-based high-temperature superconductivity in FeSe.

Discovery of orbital-selective Cooper pairing in FeSe.

The superconductor iron selenide (FeSe) is of intense interest owing to its unusual nonmagnetic nematic state and potential for high-temperature superconductivity. But its Cooper pairing mechanism has not been determined. We used Bogoliubov quasiparticle interference imaging to determine the Fermi surface geometry of the electronic bands surrounding the Γ = (0, 0) and X = (π/aFe, 0) points of FeSe and to measure the corresponding superconducting energy gaps. We show that both gaps are extremely anisotropic but nodeless and that they exhibit gap maxima oriented orthogonally in momentum space. Moreover, by implementing a novel technique, we demonstrate that these gaps have opposite sign with respect to each other. This complex gap configuration reveals the existence of orbital-selective Cooper pairing that, in FeSe, is based preferentially on electrons from the d yz orbitals of the iron atoms.

Effect of Biaxial Strain on the Phase Transitions of Ca(Fe_{1-x}Co_{x})_{2}As_{2}.

We study the effect of applied strain as a physical control parameter for the phase transitions of Ca(Fe_{1-x}Co_{x})_{2}As_{2} using resistivity, magnetization, x-ray diffraction, and ^{57}Fe Mössbauer spectroscopy. Biaxial strain, namely, compression of the basal plane of the tetragonal unit cell, is created through firm bonding of samples to a rigid substrate via differential thermal expansion. This strain is shown to induce a magnetostructural phase transition in originally paramagnetic samples, and superconductivity in previously nonsuperconducting ones. The magnetostructural transition is gradual as a consequence of using strain instead of pressure or stress as a tuning parameter.

Origin of the Resistivity Anisotropy in the Nematic Phase of FeSe.

The in-plane resistivity anisotropy is studied in strain-detwinned single crystals of FeSe. In contrast to other iron-based superconductors, FeSe does not develop long-range magnetic order below the tetragonal-to-orthorhombic transition at T_{s}≈90 K. This allows for the disentanglement of the contributions to the resistivity anisotropy due to nematic and magnetic orders. Comparing direct transport and elastoresistivity measurements, we extract the intrinsic resistivity anisotropy of strain-free samples. The anisotropy peaks slightly below T_{s} and decreases to nearly zero on cooling down to the superconducting transition. This behavior is consistent with a scenario in which the in-plane resistivity anisotropy is dominated by inelastic scattering by anisotropic spin fluctuations.

Strong cooperative coupling of pressure-induced magnetic order and nematicity in FeSe.

A hallmark of the iron-based superconductors is the strong coupling between magnetic, structural and electronic degrees of freedom. However, a universal picture of the normal state properties of these compounds has been confounded by recent investigations of FeSe where the nematic (structural) and magnetic transitions appear to be decoupled. Here, using synchrotron-based high-energy x-ray diffraction and time-domain Mössbauer spectroscopy, we show that nematicity and magnetism in FeSe under applied pressure are indeed strongly coupled. Distinct structural and magnetic transitions are observed for pressures between 1.0 and 1.7 GPa and merge into a single first-order transition for pressures ≳1.7 GPa, reminiscent of what has been found for the evolution of these transitions in the prototypical system Ba(Fe1-xCox)2As2. Our results are consistent with a spin-driven mechanism for nematic order in FeSe and provide an important step towards a universal description of the normal state properties of the iron-based superconductors.

Superconductivity-induced re-entrance of the orthorhombic distortion in Ba1-xKxFe2As2.

Detailed knowledge of the phase diagram and the nature of the competing magnetic and superconducting phases is imperative for a deeper understanding of the physics of iron-based superconductivity. Magnetism in the iron-based superconductors is usually a stripe-type spin-density-wave, which breaks the tetragonal symmetry of the lattice, and is known to compete strongly with superconductivity. Recently, it was found that in some systems an additional spin-density-wave transition occurs, which restores this tetragonal symmetry, however, its interaction with superconductivity remains unclear. Here, using thermodynamic measurements on Ba1-xKxFe2As2 single crystals, we show that the spin-density-wave phase of tetragonal symmetry competes much stronger with superconductivity than the stripe-type spin-density-wave phase, which results in a novel re-entrance of the latter at or slightly below the superconducting transition.

Infrared Study of the Spin Reorientation Transition and Its Reversal in the Superconducting State in Underdoped Ba(1-x)K(x)Fe(2)As(2).

With infrared spectroscopy we investigated the spin-reorientation transition from an orthorhombic antiferromagnetic (o-AF) to a tetragonal AF (t-AF) phase and the reentrance of the o-AF phase in the superconducting state of underdoped Ba(1-x)K(x)Fe(2)As(2). In agreement with the predicted transition from a single-Q to a double-Q AF structure, we found that a distinct spin density wave develops in the t-AF phase. The pair breaking peak of this spin density wave acquires much more low-energy spectral weight than the one in the o-AF state which indicates that it competes more strongly with superconductivity. We also observed additional phonon modes in the t-AF phase which likely arise from a Brillouin-zone folding that is induced by the double-Q magnetic structure with two Fe sublattices exhibiting different magnitudes of the magnetic moment.

Origin of the tetragonal-to-orthorhombic phase transition in FeSe: a combined thermodynamic and NMR study of nematicity.

The nature of the tetragonal-to-orthorhombic structural transition at T_{s}≈90 K in single crystalline FeSe is studied using shear-modulus, heat-capacity, magnetization, and nuclear magnetic resonance measurements. The transition is shown to be accompanied by a large shear-modulus softening, which is practically identical to that of underdoped Ba(Fe,Co)_{2}As_{2}, suggesting a very similar strength of the electron-lattice coupling. On the other hand, a spin-fluctuation contribution to the spin-lattice relaxation rate is only observed below T_{s}. This indicates that the structural, or "nematic," phase transition in FeSe is not driven by magnetic fluctuations.

Nematic susceptibility of hole-doped and electron-doped BaFe2As2 iron-based superconductors from shear modulus measurements.

The nematic susceptibility, χφ, of hole-doped Ba(1-x)K(x)Fe2As2 and electron-doped Ba(Fe(1-x)Co(x))2As2 iron-based superconductors is obtained from measurements of the elastic shear modulus using a three-point bending setup in a capacitance dilatometer. Nematic fluctuations, although weakened by doping, extend over the whole superconducting dome in both systems, suggesting their close tie to superconductivity. Evidence for quantum critical behavior of χφ is, surprisingly, only found for Ba(Fe(1-x)Co(x))2As2 and not for Ba(1-x)K(x)Fe2As2--the system with the higher maximal Tc value.

Evidence of strong correlations and coherence-incoherence crossover in the iron pnictide superconductor KFe2As2.

Using resistivity, heat-capacity, thermal-expansion, and susceptibility measurements we study the normal-state behavior of KFe2As2. Both the Sommerfeld coefficient (γ≈103 mJ mol(-1) K(-2)) and the Pauli susceptibility (χ≈4×10(-4)) are strongly enhanced, which confirm the existence of heavy quasiparticles inferred from previous de Haas-van Alphen and angle-resolved photoemission spectroscopy experiments. We discuss this large enhancement using a Gutzwiller slave-boson mean-field calculation, which shows the proximity of KFe2As2 to an orbital-selective Mott transition. The temperature dependence of the magnetic susceptibility and the thermal expansion provide strong experimental evidence for the existence of a coherence-incoherence crossover, similar to what is found in heavy fermion and ruthenate compounds, due to Hund's coupling between orbitals.

Mechanisms involved in the antinociception induced by systemic administration of guanosine in mice.

BACKGROUND AND PURPOSE: It is well known that adenine-based purines exert multiple effects on pain transmission. However, less attention has been given to the potential effects of guanine-based purines on pain transmission. The aim of this study was to investigate the effects of intraperitoneal (i.p.) and oral (p.o.) administration of guanosine on mice pain models. Additionally, investigation into the mechanisms of action of guanosine, its potential toxicity and cerebrospinal fluid (CSF) purine levels were also assessed. EXPERIMENTAL APPROACH: Mice received an i.p. or p.o. administration of vehicle (0.1 mM NaOH) or guanosine (up to 240 mg x kg(-1)) and were evaluated in several pain models. KEY RESULTS: Guanosine produced dose-dependent antinociceptive effects in the hot-plate, glutamate, capsaicin, formalin and acetic acid models, but it was ineffective in the tail-flick test. Additionally, guanosine produced a significant inhibition of biting behaviour induced by i.t. injection of glutamate, AMPA, kainate and trans-ACPD, but not against NMDA, substance P or capsaicin. The antinociceptive effects of guanosine were prevented by selective and non-selective adenosine receptor antagonists. Systemic administration of guanosine (120 mg x kg(-1)) induced an approximately sevenfold increase on CSF guanosine levels. Guanosine prevented the increase on spinal cord glutamate uptake induced by intraplantar capsaicin. CONCLUSIONS AND IMPLICATIONS: This study provides new evidence on the mechanism of action of the antinociceptive effects after systemic administration of guanosine. These effects seem to be related to the modulation of adenosine A(1) and A(2A) receptors and non-NMDA glutamate receptors.

Anti-nociceptive properties of the xanthine oxidase inhibitor allopurinol in mice: role of A1 adenosine receptors.

BACKGROUND AND PURPOSE: Allopurinol is a potent inhibitor of the enzyme xanthine oxidase, used primarily in the treatment of hyperuricemia and gout. It is well known that purines exert multiple effects on pain transmission. We hypothesized that the inhibition of xanthine oxidase by allopurinol, thereby reducing purine degradation, could be a valid strategy to enhance purinergic activity. The aim of this study was to investigate the anti-nociceptive profile of allopurinol on chemical and thermal pain models in mice. EXPERIMENTAL APPROACH: Mice received an intraperitoneal (i.p.) injection of vehicle (Tween 10%) or allopurinol (10-400 mg kg(-1)). Anti-nociceptive effects were measured with intraplantar capsaicin, intraplantar glutamate, tail-flick or hot-plate tests. KEY RESULTS: Allopurinol presented dose-dependent anti-nociceptive effects in all models. The opioid antagonist naloxone did not affect these anti-nociceptive effects. The non-selective adenosine-receptor antagonist caffeine and the selective A(1) adenosine-receptor antagonist, DPCPX, but not the selective A(2A) adenosine-receptor antagonist, SCH58261, completely prevented allopurinol-induced anti-nociception. No obvious motor deficits were produced by allopurinol, at doses up to 200 mg kg(-1). Allopurinol also caused an increase in cerebrospinal fluid levels of purines, including the nucleosides adenosine and guanosine, and decreased cerebrospinal fluid concentration of uric acid. CONCLUSIONS AND IMPLICATIONS: Allopurinol-induced anti-nociception may be related to adenosine accumulation. Allopurinol is an old and extensively used compound and seems to be well tolerated with no obvious central nervous system toxic effects at high doses. This drug may be useful to treat pain syndromes in humans.