The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.

Ligation and transection of the L5 spinal nerve in the rat lead to behavioral signs of pain and hyperalgesia. Discharge of injured nociceptors has been presumed to play a role in generating the pain. However, A fibers, but not C fibers, in the injured L5 spinal nerve have been shown to develop spontaneous activity. Moreover, an L5 dorsal root rhizotomy does not reverse this pain behavior, suggesting that signals from other uninjured spinal nerves are involved. We asked if abnormal activity develops in an adjacent, uninjured root. Single nerve fiber recordings were made from the L4 spinal nerve after ligation and transection of the L5 spinal nerve. Within 1 d of the lesion, spontaneous activity developed in approximately half of the C fiber afferents. This spontaneous activity was at a low level (median rate, seven action potentials/5 min), originated distal to the dorsal root ganglion, and was present in nociceptive fibers with cutaneous receptive fields. The incidence and level of spontaneous activity were similar 1 week after injury. The early onset of spontaneous activity in uninjured nociceptive afferents could be the signal that produces the central sensitization responsible for the development of mechanical hyperalgesia. Because L4 afferents comingle with degenerating L5 axons in the peripheral nerve, we hypothesize that products associated with Wallerian degeneration lead to an alteration in the properties of the adjacent, uninjured afferents.

We demonstrated recently that uninjured C-fiber nociceptors in the L4 spinal nerve develop spontaneous activity after transection of the L5 spinal nerve. We postulated that Wallerian degeneration leads to an alteration in the properties of the neighboring, uninjured afferents from adjacent spinal nerves. To explore the role of degeneration of myelinated versus unmyelinated fibers, we investigated the effects of an L5 ventral rhizotomy in rat. This lesion leads to degeneration predominantly in myelinated fibers. Mechanical paw-withdrawal thresholds were assessed with von Frey hairs, and teased-fiber techniques were used to record from single C-fiber afferents in the L4 spinal nerve. Behavioral and electrophysiological data were collected in a blinded manner. Seven days after surgery, a marked decrease in withdrawal thresholds was observed after the ventral rhizotomy but not after the sham operation. Single fiber recordings revealed low-frequency spontaneous activity in 25% of the C-fiber afferents 8-10 d after the lesion compared with only 11% after sham operation. Paw-withdrawal thresholds were inversely correlated with the incidence of spontaneous activity in high-threshold C-fiber afferents. In normal animals, low-frequency electrocutaneous stimulation at C-fiber, but not A-fiber, strength produced behavioral signs of secondary mechanical hyperalgesia on the paw. These results suggest that degeneration in myelinated efferent fibers is sufficient to induce spontaneous activity in C-fiber afferents and behavioral signs of mechanical hyperalgesia. Ectopic spontaneous activity from injured afferents was not required for the development of the neuropathic pain behavior. These results provide additional evidence for a role of Wallerian degeneration in neuropathic pain.

Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ϳ1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.

The wide implications of NPY in psychiatric disorders such as depression and PTSD make the NPYergic system a promising target for the development of novel therapeutic interventions. These include intranasal NPY administration, currently under study, and the development of agonists and antagonists targeting NPY receptors. Therefore, we are proposing that via this mode of administration, NPY might exert CNS therapeutic actions without untoward systemic effects. Future work will show if this is a feasible approach.