Radiative BB to axial-vector meson decays at NLO in Soft-Collinear Effective Theory

The rare decay $B\rightarrow A\gamma$, with $A$ representing axial-vector mesons such as $K_1 (1270),\; K_1 (1400),\; b_1(1300),\; a_1(1260)$, is studied at next-to-leading order (NLO) in soft collinear effective theory (SCET). The large outgoing meson energy encourages the study of the decay with an appropriate factorization scheme that separates the factorizable and non-factorizable parts systematically. We have analyzed the leading-power and $\mathcal{O}(\alpha_s)$ diagrams that contribute to matching to SCET$_I$. The new intermediate theory is matched onto SCET$_{II}$ and the running of SCET$_I$ operators is performed to sum large perturbative logarithms. The values of soft-overlap function $\zeta_{\perp}$ for $K_1 (1270,\;1400), a_{1}$ and $b_{1}$ mesons are estimated from the light cone-sum-rules (LCSR), and later using it the corresponding branching fractions for $B \to \left(K_{1}(1270,\; 1400),\; a_{1},\; b_{1}\right)\gamma$ decays are calculated. We find that in case of $B \to K_{1}(1270,\; 1400)\gamma$ decays the results are in good agreement with their experimental measurements. Also the estimated values of the branching ratios of the $B \to (b_{1},\; a_1)\gamma$ decays are potentially large to be measured at the LHCb and future B-factories

Chemogenetic silencing of NaV1.8 positive sensory neurons reverses chronic neuropathic and bone cancer pain in FLEx PSAM4-GlyR mice

Drive from peripheral neurons is essential in almost all pain states, but pharmacological silencing of these neurons to effect analgesia has proved problematic. Reversible gene therapy using long-lived chemogenetic approaches is an appealing option. We used the genetically-activated chloride channel PSAM4-GlyR to examine pain pathways in mice. Using recombinant AAV9-based delivery to sensory neurons, we found a reversal of acute pain behavior and diminished neuronal activity using in vitro and in vivo GCaMP imaging upon activation of PSAM4-GlyR with varenicline. A significant reduction in inflammatory heat hyperalgesia and oxaliplatin-induced cold allodynia was also observed. Importantly, there was no impairment of motor coordination, but innocuous von Frey sensation was inhibited. We generated a transgenic mouse that expresses a CAG-driven FLExed PSAM4-GlyR downstream of the Rosa26 locus that requires Cre recombinase to enable the expression of PSAM4-GlyR and tdTomato. We used NaV1.8 Cre to examine the role of predominantly nociceptive NaV1.8+ neurons in cancer-induced bone pain (CIBP) and neuropathic pain caused by chronic constriction injury (CCI). Varenicline activation of PSAM4-GlyR in NaV1.8-positive neurons reversed CCI-driven mechanical, thermal, and cold sensitivity. Additionally, varenicline treatment of mice with CIBP expressing PSAM4-GlyR in NaV1.8+ sensory neurons reversed cancer pain as assessed by weight-bearing. Moreover, when these mice were subjected to acute pain assays, an elevation in withdrawal thresholds to noxious mechanical and thermal stimuli was detected, but innocuous mechanical sensations remained unaffected. These studies confirm the utility of PSAM4-GlyR chemogenetic silencing in chronic pain states for mechanistic analysis and potential future therapeutic use.Significance StatementChronic pain is a massive problem. Peripheral nerve block is effective in many chronic pain conditions, demonstrating the importance of peripheral drive in chronic pain. We used chemogenetic tools based on the modified ligand-gated chloride channel PSAM4-GlyR to silence dorsal root ganglion neurons in vitro and in vivo This approach reduces pain-like behavior in acute and chronic pain models, including resistant pain conditions like neuropathic pain or cancer-induced bone pain. We generated a mouse line that expresses PSAM4-GlyR in a Cre-dependent manner, providing a useful research tool to address not only the role of nociceptive sensory neurons in pain states but also the function of genetically defined sets of neurons throughout the nervous system in normal and pathological conditions

Gate control of sensory neurotransmission in peripheral ganglia by proprioceptive sensory neurons

Melzak and Wall's gate control theory proposed that innocuous input into the dorsal horn of the spinal cord represses pain-inducing nociceptive input. Here we show that input from proprioceptive parvalbumin-expressing sensory neurons tonically represses nociceptor activation within dorsal root ganglia. Deletion of parvalbumin-positive sensory neurons leads to enhanced nociceptor activity measured with GCaMP3, increased input into wide dynamic range neurons of the spinal cord and increased acute and spontaneous pain behaviour, as well as potentiated innocuous sensation. Parvalbumin-positive sensory neurons express the enzymes and transporters necessary to produce vesicular GABA that is known to be released from depolarized somata. These observations support the view that gate control mechanisms occur peripherally within dorsal root ganglia

Pregabalin Suppresses Spinal Neuronal Hyperexcitability and Visceral Hypersensitivity in the Absence of Peripheral Pathophysiology

ABSTRACT Background: Opioid-induced hyperalgesia is recognized in the laboratory and the clinic, generating central hyperexcitability in the absence of peripheral pathology. We investigated pregabalin, indicated for neuropathic pain, and ondansetron, a drug that disrupts descending serotonergic processing in the central nervous system, on spinal neuronal hyperexcitability and visceral hypersensitivity in a rat model of opioid-induced hyperalgesia. Methods: Male Sprague-Dawley rats (180 -200 g) were implanted with osmotic mini-pumps filled with morphine (90 g ⅐ l Ϫ1 ⅐

Sensitization of Cutaneous Primary Afferents in Bone Cancer Revealed by In Vivo Calcium Imaging

Cancer-induced bone pain (CIBP) is a complex condition, comprising components of inflammatory and neuropathic processes, but changes in the physiological response profiles of bone-innervating and cutaneous afferents remain poorly understood. We used a combination of retrograde labelling and in vivo calcium imaging of bone marrow-innervating dorsal root ganglia (DRG) neurons to determine the contribution of these cells in the maintenance of CIBP. We found a majority of femoral bone afferent cell bodies in L3 dorsal root ganglia (DRG) that also express the sodium channel subtype Nav1.8—a marker of nociceptive neurons—and lack expression of parvalbumin—a marker for proprioceptive primary afferents. Surprisingly, the response properties of bone marrow afferents to both increased intraosseous pressure and acid were unchanged by the presence of cancer. On the other hand, we found increased excitability and polymodality of cutaneous afferents innervating the ipsilateral paw in cancer bearing animals, as well as a behavioural phenotype that suggests changes at the level of the DRG contribute to secondary hypersensitivity. This study demonstrates that cutaneous afferents at distant sites from the tumour bearing tissue contribute to mechanical hypersensitivity, highlighting these cells as targets for analgesia

Effect of the spider toxin Tx3-3 on spinal processing of sensory information in naive and neuropathic rats: an in vivo electrophysiological study

Abstract. Introduction:. Drugs that counteract nociceptive transmission in the spinal dorsal horn preferentially after nerve injury are being pursued as possible neuropathic pain treatments. In a previous behavioural study, the peptide toxin Tx3-3, which blocks P/Q- and R-type voltage-gated calcium channels, was effective in neuropathic pain models. Objectives:. In the present study, we aimed to investigate the effect of Tx3-3 on dorsal horn neuronal responses in rats under physiological conditions and neuropathic pain condition induced by spinal nerve ligation (SNL). Methods:. In vivo electrophysiological recordings of dorsal horn neuronal response to electrical and natural (mechanical and thermal) stimuli were made in rats under normal physiological state (naive rats) or after the SNL model of neuropathic pain. Results:. Tx3-3 (0.3–100 pmol/site) exhibited greater inhibitory effect on electrical-evoked neuronal response of SNL rats than naive rats, inhibiting nociceptive C-fibre and Aδ-fibre responses only in SNL rats. The wind-up of neurones, a measurement of spinal cord hyperexcitability, was also more susceptible to a dose-related inhibition by Tx3-3 after nerve injury. Moreover, Tx3-3 exhibited higher potency to inhibit mechanical- and thermal-evoked neuronal response in conditions of neuropathy. Conclusion:. Tx3-3 mediated differential inhibitory effect under physiological and neuropathic conditions, exhibiting greater potency in conditions of neuropathic pain

Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models

ABSTRACT: The predictive value of laboratory models for human pain processing is crucial for improving translational research. The discrepancy between peripheral and central mechanisms of pain is an important consideration for drug targets, and here we describe two models of inflammatory pain that involve ultraviolet B (UVB) irradiation, which can employ peripheral and central sensitisation to produce mechanical and thermal hyperalgesia in rats and humans. We use electrophysiology in rats to measure the mechanically- and thermally-evoked activity of rat spinal neurones and quantitative sensory testing to assess human psychophysical responses to mechanical and thermal stimulation in a model of UVB irradiation and in a model of UVB irradiation with heat rekindling. Our results demonstrate peripheral sensitisation in both species driven by UVB irradiation, with a clear mechanical and thermal hypersensitivity of rat dorsal horn neurones and enhanced perceptual responses of human subjects to both mechanical and thermal stimulation. Additional heat rekindling produces markers of central sensitisation in both species, including enhanced receptive field sizes. Importantly, we also showed a correlation in the evoked activity of rat spinal neurones to human thermal pain thresholds. The parallel results in rats and humans validate the translational use of both models and the potential for such models for preclinical assessment of prospective analgesics in inflammatory pain states. KEY POINTS: Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. . We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology and human quantitative sensory testing to characterise nociceptive processing in the peripheral and central nervous systems in both models. . In both species, UVB irradiation produces peripheral sensitisation measured as augmented evoked activity of rat dorsal horn neurones and increased perceptual responses of human subjects to mechanical and thermal stimuli. . In both species, UVB with heat rekindling produces central sensitisation. . UVB irradiation alone and UVB with heat rekindling are translational models of inflammation that produce peripheral and central sensitisation, respectively.