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.

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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.

Ethenzamide (ETZ), an antipyretic analgesic categorized as a non-steroidal anti-inflammatory drug (NSAID), is widely used as an over-the-counter (OTC) drug in combination with other NSAIDs. However, its site of action and mechanism underlying its analgesic action have not yet been fully elucidated. In this study, we performed in vitro pharmacological assays to identify the mechanism underlying the analgesic action of ETZ, and also conducted the rat formalin test to investigate its analgesic effect and site of action.Of the 85 receptors, ion channels, transporters and enzymes tested, we found that ETZ binds to the 5-hydroxytryptamine (5HT) 2B receptor in concentration-dependent manner with modest inhibitory effects on monoamine oxidase-A and transient potential vanilloid 1 channel. The 5HT 2B receptor antagonist activity of ETZ was also confirmed in a cellular functional assay. Furthermore, the drug exerted no inhibitory effects on cycrooxygenase-1 and -2. In the rat formalin test, oral administration of ETZ significantly reduced the nociceptive responses of the second phase and also the number of c-Fos-expressing cells in the spinal dorsal horn, in a dose-dependent manner. Moreover, intrathecal administration of ETZ significantly reduced the nociceptive responses. These results suggest that the analgesic effect of ETZ is exerted at least in the spinal cord, and the effect would be attributed to multiple mechanisms of action including 5HT 2B receptor blockade.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause gastric mucosal damage, in which gastric hypermotility has been reported to play a primary role. The antipyretic analgesic drug ethenzamide (ETZ) is widely used in combination with other NSAIDs and, in a recent study, was found to possess 5hydroxytriptamine (5HT) 2B receptor antagonistic activity. Therefore, the inhibition of gastric contraction via 5HT 2B receptor blockade by ETZ might contribute to ETZ's protective effect against NSAIDs-induced gastric mucosal damage. In the present study, we examined the effects of ETZ on gastric contraction and ibuprofen (IBP)-induced gastric mucosal damage in rats. We found that ETZ suppressed both 5HT-and α-methyl-5HT (5HT 2 receptor agonist)-induced contractions of rat-isolated gastric fundus in a concentration-dependent manner. This suppressive effect of ETZ was not seen for either high-KCl-or acetylcholine-induced contractions. Furthermore, ETZ was confirmed to decrease ibuprofen-induced gastric mucosal damage in a dosedependent manner in rats. Similarly, clonidine is known to reduce gastric motility, and methysergide (a 5HT 2 receptor antagonist) is known to inhibit 5HT-induced contractions of the gastric fundus, which also decreases IBP-induced gastric mucosal damage, respectively. Although further research on other possible sites or mechanisms of action would be needed, these results suggest that ETZ exerts a protective effect against IBPinduced gastric mucosal damage and that suppressing the gastric contraction may play an important role in the gastroprotective effect of ETZ.