Satoshi Deyama

Activation of the β-Adrenoceptor–Protein Kinase A Signaling Pathway within the Ventral Bed Nucleus of the Stria Terminalis Mediates the Negative Affective Component of Pain in Rats

Pain is an unpleasant sensory and emotional experience. The neural systems underlying the sensory component of pain have been studied extensively, but we are only beginning to understand those underlying its affective component. The bed nucleus of the stria terminalis (BNST) has been implicated in stress responses and negative affective states, such as anxiety, fear, and aversion. Recently, we demonstrated the crucial role of the BNST in the negative affective component of pain using the conditioned place aversion (CPA) test. In the present study, we investigated the involvement of the β-adrenoceptor–protein kinase A (PKA) signaling pathway within the BNST, in particular, within the ventral part of the BNST (vBNST), in pain-induced aversion in male Sprague Dawley rats. In vivo microdialysis showed that extracellular noradrenaline levels within the vBNST were significantly increased by intraplantar formalin injection. Using the CPA test, we found that intra-vBNST injection of timolol, a β-adrenoceptor antagonist, dose-dependently attenuated the intraplantar-formalin-induced CPA (F-CPA) without reducing nociceptive behaviors. Experiments with subtype-selective antagonists demonstrated the essential role of β2-adrenoceptors in F-CPA. Intra-vBNST injection of isoproterenol, a β-adrenoceptor agonist, dose-dependently produced CPA even in the absence of noxious stimulation. This isoproterenol-induced CPA was reversed by the coinjection of Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS), a selective PKA inhibitor. Furthermore, intra-vBNST injection of Rp-cAMPS dose-dependently attenuated the F-CPA. Together, these results suggest that PKA activation within the vBNST via the enhancement of β-adrenergic transmission is important for the negative affective component of pain.

Involvement of the bed nucleus of the stria terminalis in the negative affective component of visceral and somatic pain in rats.

Using a conditioned place paradigm, we examined the involvement of the bed nucleus of the stria terminalis (BST) in the negative affective component of visceral and somatic pain induced by intraperitoneal acetic acid and intraplantar formalin injections, respectively, in rats. Bilateral BST lesions suppressed both the acetic acid- and formalin-induced conditioned place aversion, suggesting the crucial role of the BST in the negative affective component of visceral and somatic pain.

Role of enhanced noradrenergic transmission within the ventral bed nucleus of the stria terminalis in visceral pain-induced aversion in rats

Pain is an unpleasant sensory and emotional experience. We demonstrated the crucial role of the bed nucleus of the stria terminalis (BNST) in the negative affective component of somatic and visceral pain induced by intraplantar formalin and intraperitoneal acetic acid injections, respectively, in rats. Recently, we reported the involvement of enhanced noradrenergic transmission via beta-adrenoceptors within the ventral BNST (vBNST) in formalin-induced aversion. Here, we examined the role of intra-vBNST noradrenergic transmission in the negative affective component of visceral pain induced by intraperitoneal acetic acid injection. In vivo microdialysis showed that extracellular noradrenaline levels within the vBNST significantly increased after intraperitoneal acetic acid injection. Using a conditioned place aversion (CPA) test, we found that intra-vBNST injection of timolol, a beta-adrenoceptor antagonist, dose-dependently attenuated the acetic acid-induced CPA without reducing nociceptive behaviors. These results suggest that enhanced noradrenergic transmission via beta-adrenoceptors within the vBNST plays a pivotal role in the negative affective, but not sensory, component of visceral pain.

Inhibition of glutamatergic transmission by morphine in the basolateral amygdaloid nucleus reduces pain-induced aversion

We examined the role of glutamatergic transmission within the basolateral amygdaloid nucleus (BLA) in pain-induced aversion using a conditioned place paradigm and an in vivo microdialysis technique in rats. Microinjection of MK-801 (1 or 10 nmol/side) into the bilateral BLA 5 min before intraplantar injection of formalin dose-dependently attenuated formalin-induced conditioned place aversion (F-CPA) without affecting nociceptive behaviors, such as lifting, licking, and biting. On the contrary, microinjection of neither CNQX (30 nmol/side) nor AP-3 (30 nmol/side) showed any significant effect on F-CPA. Microdialysis experiments revealed that intraplantar injection of formalin induced an increase in the extracellular glutamate level within the BLA. This increase in glutamate was suppressed by morphine perfusion (100 microM) via the microdialysis probe. Moreover, intra-BLA injection of morphine (10 microg/side) 5 min before formalin injection attenuated F-CPA without affecting nociceptive behaviors. These results suggest that glutamatergic transmission via NMDA receptors in the BLA plays a crucial role in the pain-induced aversion, and that in addition to the well-characterized effects on the sensory component of pain, morphine also influences the affective component of pain through an inhibitory effect on intra-BLA glutamatergic transmission.

Resolvin D1 and D2 Reverse Lipopolysaccharide-Induced Depression-Like Behaviors Through the mTORC1 Signaling Pathway

Abstract Background: Resolvin D1 and D2 are bioactive lipid mediators that are generated from docosahexaenoic acid. Although recent preclinical studies suggest that these compounds have antidepressant effects, their mechanisms of action remain unclear. Methods: We investigated mechanisms underlying the antidepressant effects of resolvin D1 and resolvin D2 in lipopolysaccharide (0.8 mg/kg, i.p.)-induced depression model mice using a tail suspension test. Results: I.c.v. infusion of resolvin D1 (10 ng) and resolvin D2 (10 ng) produced antidepressant effects; these effects were significantly blocked by a resolvin D1 receptor antagonist WRW4 (10 µg, i.c.v.) and a resolvin D2 receptor antagonist O-1918 (10 µg, i.c.v.), respectively. The mammalian target of rapamycin complex 1 inhibitor rapamycin (10 mg/kg, i.p.) and a mitogen-activated protein kinase kinase inhibitor U0126 (5 µg, i.c.v.) significantly blocked the antidepressant effects of resolvin D1 and resolvin D2. An AMPA receptor antagonist NBQX (10 mg/kg, i.p.) and a phosphoinositide 3-kinase inhibitor LY294002 (3 µg, i.c.v.) blocked the antidepressant effects of resolvin D1 significantly, but not of resolvin D2. Bilateral infusions of resolvin D1 (0.3 ng/side) or resolvin D2 (0.3 ng/side) into the medial prefrontal cortex or dentate gyrus of the hippocampus produced antidepressant effects. Conclusions: These findings demonstrate that resolvin D1 and resolvin D2 produce antidepressant effects via the mammalian target of rapamycin complex 1 signaling pathway, and that the medial prefrontal cortex and dentate gyrus are important brain regions for these antidepressant effects. These compounds and their receptors may be promising targets for the development of novel rapid-acting antidepressants, like ketamine and scopolamine.

Rapid and sustained antidepressant effects of resolvin D1 and D2 in a chronic unpredictable stress model

Resolvin D1 (RvD1) and D2 (RvD2) are lipid mediators that are derived from docosahexaenoic acid. We recently demonstrated that intracerebroventricular (i.c.v.) infusions of RvD1 or RvD2 attenuate lipopolysaccharide-induced depression-like behaviors via mammalian target of rapamycin complex 1 signaling. However, the antidepressant effects of RvD1 and RvD2 have not been fully investigated. Here, we examined the antidepressant effects of RvD1 and RvD2 using the tail suspension test (TST) and forced swim test (FST) in murine chronic unpredictable stress (CUS) model. Male BALB/c mice (7 weeks) were subjected to 5 weeks of CUS and then received with a single i.c.v. infusion of RvD1 (10ng), RvD2 (10ng), or vehicle. In vehicle-infused mice, CUS significantly increased immobility in the TST both 2 and 24h after i.c.v. infusion, these depression-like behaviors were significantly ameliorated by RvD1 or RvD2. Similar results were obtained from the FST. Intracerebroventricular infusion of RvD1 or RvD2 did not affect locomotor activity. These results demonstrate that RvD1 and RvD2 produce rapid and sustained antidepressant effects in the CUS model.

Activation of the NMDA receptor–neuronal nitric oxide synthase pathway within the ventral bed nucleus of the stria terminalis mediates the negative affective component of pain

ABSTRACT Pain consists of sensory and affective components. Although the neuronal mechanisms underlying the sensory component of pain have been studied extensively, those underlying its affective component are only beginning to be elucidated. Previously, we showed the pivotal role of the ventral part of the bed nucleus of the stria terminalis (vBNST) in the negative affective component of pain. Here, we examined the role of glutamate‐nitric oxide (NO) signaling in the affective component of pain in rats using a conditioned place aversion (CPA) test. Intra‐vBNST injection of either CNQX (an AMPA receptor antagonist) or MK‐801 (an NMDA receptor antagonist) dose‐dependently attenuated intraplantar formalin‐induced CPA (F‐CPA) without reducing nociceptive behaviors. In vivo microdialysis showed that extracellular oxidative NO metabolites (NOx) levels were significantly increased by intraplantar formalin injection. Intra‐vBNST injection of NPLA (a selective neuronal NO synthase (nNOS) inhibitor), c‐PTIO (a NO scavenger), or ZL006 (a postsynaptic density‐95 (PSD‐95)‐nNOS interaction inhibitor) dose‐dependently suppressed F‐CPA without attenuating nociceptive behaviors. Intra‐vBNST injection of NOR3 (a NO donor) produced CPA in a dose‐dependent manner in the absence of noxious stimulation. Furthermore, whole‐cell patch‐clamp electrophysiology in the vBNST slices revealed that NOR3 induced depolarization of hyperpolarization‐activated cation current (Ih)‐positive vBNST neurons, which was blocked by the NO scavenger. These results suggest that activation of glutamatergic transmission and subsequent nNOS‐derived NO production within the vBNST mediate the negative affective component of pain and that NO‐evoked excitation of Ih‐positive vBNST neurons may be among the cellular mechanisms underlying pain‐induced aversion. HIGHLIGHTSBlockade of glutamatergic transmission in the vBNST reduces pain‐induced aversion.Painful stimulus increases NO metabolites in the vBNST.Blockade of nNOS‐derived NO in the vBNST reduces pain‐induced aversion.Intra‐vBNST injection of NO donor produces aversion.NO‐evoked excitation of vBNST neurons may be critical for pain‐induced aversion.

Suppressive effects of morphine injected into the ventral bed nucleus of the stria terminalis on the affective, but not sensory, component of pain in rats

Pain is a complex experience with both sensory and affective components. Clinical and preclinical studies have shown that the affective component of pain can be reduced by doses of morphine lower than those necessary to reduce the sensory component. Although the neural mechanisms underlying the effects of morphine on the sensory component of pain have been investigated extensively, those influencing the affective component remain to be elucidated. The bed nucleus of the stria terminalis (BNST) has been implicated in the regulation of various negative emotional states, including aversion, anxiety and fear. Thus, this study aimed to clarify the role of the ventral part of the BNST (vBNST) in the actions of morphine on the affective and sensory components of pain. First, the effects of intra‐vBNST injections of morphine on intraplantar formalin‐induced conditioned place aversion (CPA) and nociceptive behaviors were investigated. Intra‐vBNST injections of morphine reduced CPA without affecting nociceptive behaviors, which suggests that intra‐vBNST morphine alters the affective, but not sensory, component of pain. Next, to examine the effects of morphine on neuronal excitability in type II vBNST neurons, whole‐cell patch‐clamp recordings were performed in brain slices. Bath application of morphine hyperpolarized type II vBNST neurons. Thus, the suppressive effects of intra‐vBNST morphine on pain‐induced aversion may be due to its inhibitory effects on neuronal excitability in type II vBNST neurons. These results suggest that the vBNST is a key brain region involved in the suppressive effects of morphine on the affective component of pain.