Pain is a complex experience composed of sensory and affective components. Although the neural systems of the sensory component of pain have been studied extensively, those of its affective component remain to be determined. In the present study, we examined the effects of corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) injected into the dorsolateral bed nucleus of the stria terminalis (dlBNST) on pain-induced aversion and nociceptive behaviors in rats to examine the roles of these peptides in affective and sensory components of pain, respectively. In vivo microdialysis showed that formalin-evoked pain enhanced the release of CRF in this brain region. Using a conditioned place aversion (CPA) test, we found that intra-dlBNST injection of a CRF 1 or CRF 2 receptor antagonist suppressed pain-induced aversion. IntradlBNST CRF injection induced CPA even in the absence of pain stimulation. On the other hand, intra-dlBNST NPY injection suppressed paininduced aversion. Coadministration of NPY inhibited CRF-induced CPA. This inhibitory effect of NPY was blocked by coadministration of a Y 1 or Y 5 receptor antagonist. Furthermore, whole-cell patch-clamp electrophysiology in dlBNST slices revealed that CRF increased neuronal excitability specifically in type II dlBNST neurons, whereas NPY decreased it in these neurons. Excitatory effects of CRF on type II dlBNST neurons were suppressed by NPY. These results have uncovered some of the neuronal mechanisms underlying the affective component of pain by showing opposing roles of intra-dlBNST CRF and NPY in pain-induced aversion and opposing actions of these peptides on neuronal excitability converging on the same target, type II neurons, within the dlBNST.

Canagliflozin, a selective sodium/glucose cotransporter (SGLT) 2 inhibitor, suppresses the renal reabsorption of glucose and decreases blood glucose level in patients with type 2 diabetes. A characteristic of canagliflozin is its modest SGLT1 inhibitory action in the intestine at clinical dosage. To reveal its mechanism of action, we investigated the interaction of canagliflozin with SGLT1 and SGLT2. Inhibition kinetics and transporter-mediated uptake were examined in human SGLT1-or SGLT2-expressing cells. Whole-cell patch-clamp recording was conducted to examine the sidedness of drug action. Canagliflozin competitively inhibited SGLT1 and SGLT2, with high potency and selectivity for SGLT2. Inhibition constant (K i ) values for SGLT1 and SGLT2 were 770.5 and 4.0 nM, respectively. 14 C-canagliflozin was suggested to be transported by SGLT2; however, the transport rate was less than that of a-methyl-D-glucopyranoside. Canagliflozin inhibited a-methyl-D-glucopyranoside-induced SGLT1-and SGLT2-mediated inward currents preferentially from the extracellular side and not from the intracellular side. Based on the K i value, canagliflozin is estimated to sufficiently inhibit SGLT2 from the urinary side in renal proximal tubules. The K i value for SGLT1 suggests that canagliflozin suppresses SGLT1 in the small intestine from the luminal side, whereas it does not affect SGLT1 in the heart and skeletal muscle, considering the maximal concentration of plasma-unbound canagliflozin. Similarly, SGLT1 in the kidney would not be inhibited, thereby aiding in the prevention of hypoglycemia. After binding to SGLT2, canagliflozin may be reabsorbed by SGLT2, which leads to the low urinary excretion and prolonged drug action of canagliflozin.

Sarcopenia is an age-related loss of skeletal muscle associated with adverse outcomes such as falls, fractures, disability, and increased mortality in older people and hospitalized patients. About half of older male nursing home residents have sarcopenia. The diagnostic criteria by the European Working Group on Sarcopenia in Older People (EWGSOP) and the Asian Working Group for Sarcopenia (AWGS) have led to increased interest in sarcopenia. Exercise and nutritional management are crucial for the prevention and treatment of sarcopenia. Nutritional therapy for sarcopenia that includes 20 g of whey protein and 800 IU of vitamin D twice a day improves lower limb strength. Exercise therapy for sarcopenia, such as resistance training and 6 months of home exercises, improves muscle strength and physical function. Combination therapy that includes both nutritional and exercise therapy improves gait speed and knee extension strength more than either exercise alone or nutrition therapy alone. Excessive bedrest and mismanagement of nutrition in medical facilities can lead to iatrogenic sarcopenia. Iatrogenic sarcopenia is sarcopenia caused by the activities of health care workers in health care facilities. Appropriate nutritional management and exercise programs through rehabilitation nutrition are important for prevention and treatment of iatrogenic sarcopenia. Nutritional and exercise therapy should be started very early after admission and adjusted to the level of inflammation and disease status. Repeated assessment, diagnosis, goal setting, interventions, and monitoring using the rehabilitation nutrition care process is important to maximize treatment effectiveness and improve patients' functional recovery and quality of life.

Pain is a complex experience involving sensory and affective components. Although the neuronal mechanisms underlying the sensory component of pain have been extensively studied, those underlying its affective component have yet to be elucidated. Recently, we reported that corticotrophin-releasing factor (CRF)-induced depolarization in type II neurons within the dorsolateral bed nucleus of the stria terminalis (dlBNST) is critical for pain-induced aversive responses in rats. However, the intracellular signaling underlying the excitatory effects of CRF and the contribution of such signaling to the induction of pain-induced aversion remain unclear. In the present study, we addressed these issues by conducting whole-cell patch-clamp recordings in rat brain slices and by undertaking behavioral pharmacological analyses. Intracellular perfusion of protein kinase A (PKA) inhibitor Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS) or KT5720 suppressed the excitatory effects of CRF in type II dlBNST neurons, and bath application of Rp-cAMPS also suppressed it. In addition, bath application of forskolin, an adenylate cyclase (AC) activator, mimicked the effects of CRF, and pretreatment with forskolin diminished the excitatory effects of CRF. Furthermore, a conditioned place aversion (CPA) test showed that co-administration of Rp-cAMPS with CRF into the dlBNST suppressed CRF-induced CPA. Intra-dlBNST injection of Rp-cAMPS also suppressed pain-induced CPA. These results suggest that CRF increases excitability of type II dlBNST neurons through activation of the AC-cAMP-PKA pathway, thereby causing pain-induced aversive responses. The present findings shed light on the neuronal mechanisms underlying the negative affective component of pain and may provide therapeutic targets for treating intractable pain accompanied by psychological factors.

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