The nucleus accumbens (NAc) is central to heroin addiction. Activation of opiate receptors in the NAc dissociates Gi/o into ␣ and ␤␥ subunits. G␣i inhibits cAMP production, but ␤␥ regulates several molecular pathways, including protein kinase A (PKA). We show in NAc͞striatal neurons that opiates paradoxically activate PKA signaling by means of ␤␥ dimers. Activation requires G␣i3 and an activator of G protein signaling 3 (AGS3). AGS3 competes with ␤␥ for binding to G␣i3-GDP and enhances the action of unbound ␤␥. AGS3 and G␣i3 knockdown prevents opiate activation of PKA signaling. In rats self-administering heroin, AGS3 antisense in the NAc core, but not shell, eliminates reinstatement of heroin-seeking behavior, a model of human relapse. Thus, G␣i3͞␤␥͞AGS3 appears to mediate opiate receptor activation of PKA signaling as well as heroin-seeking behavior.opiate receptor ͉ nucleus accumbens core ͉ addiction ͉ ␤␥ subunits ͉ G␣i3 H eroin addiction, a worldwide socioeconomic and public health problem, is difficult for physicians to treat, often because addicts frequently relapse when they try to stop using heroin during abstinence. Heroin activates opiate receptors (1). However, we do not understand the postsynaptic cellular mechanisms produced by opiate receptor (MOR) activation that contribute to craving for and relapse to heroin. Sharma et al. (2) provided pioneering evidence in NG108-15 cells that ␦ opiate receptor (DOR) activation initially decreases cAMP levels, followed by restoration of cAMP to normal levels during continued exposure to morphine; cAMP increases further in response to opiate receptor blockade. Many investigators have confirmed an opiate-induced increase of cAMP͞protein kinase A (PKA) signaling that is exaggerated upon opiate withdrawal (3, 4). In vivo, increased cAMP͞PKA activity may be associated with opiate-induced tolerance and dependence and is thought to contribute to the reinforcing properties of opiates (5).Postsynaptic G i/o -coupled opiate receptors are expressed on GABAergic medium spiny neurons in the nucleus accumbens (NAc), a brain region thought to account, in part, for craving, reward, and reinforcement of addicting drugs (6, 7). MOR and DOR activation dissociates heterotrimeric G i/o proteins into free ␣ and ␤␥ subunits. G␣ i released from G i/o ␤␥ inhibits several isoforms of adenylyl cyclase (AC) (8) and appears to account for opiate inhibition of cAMP production. By contrast, ␤␥ dimers, which are simultaneously released during receptor activation, can stimulate AC2 and AC4 (9-13). However, the precise molecular mechanisms that facilitate this paradoxical G i/ocoupled opiate receptor-induced stimulation of cAMP͞PKA signaling are not clearly understood.Recent evidence suggests that an activator of G protein signaling 3 (AGS3) regulates G protein signaling in the NAc (14). By competing with ␤␥ for binding to G␣ i3 , AGS3 appears to stabilize a specific G␣ i3 -GDP complex formed before the reassociation of free G␣ i3 and ␤␥ subunits (15). The bound form of G␣ i3 does not inhibit...

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We present two cases of specific wheat-dependent anaphylaxis induced by aspirin but not by exercise. We suggest that pretreatment with aspirin under controlled conditions is useful to confirm the diagnosis of food allergy when a challenge test with food alone or with food and exercise fails to induce positive reactions.

Imatinib has dramatically improved long-term survival of chronic myelogenous leukemia (CML) patients. To analyze its efficacy in a practical setting, we registered most of CML patients in Nagasaki Prefecture of Japan. Of these, 73 patients received imatinib as an initial therapy. The overall survival rate of these patients was 88.7% at 6 years, and the cumulative complete cytogenetic response rate was 82.5% at 18 months. These results are comparable with the data of other reports including the IRIS study; however, the administered imatinib dose was smaller in our study than that in other reports. To address these discrepancies, we measured the trough concentration of imatinib among 35 patients. Although 39% of the patients were administered less than 400 mg/day, the trough level was comparable to those of previous reports. The trough level of imatinib showed a significant relationship with its efficacy, and was clearly related to dose of imatinib administrated and dose of imatinib divided by body surface area (BSA). Considering the smaller BSA of Japanese patients as compared to those of foreign origin, the results suggest that a lower dose of imatinib could maintain enough trough level and provided excellent results for the treatment of CML in our registry.

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To evaluate the efficacy of imatinib in a practical setting, we registered 43 patients with newly diagnosed chronic myelogenous leukemia (CML) (group I) and 56 patients with previously diagnosed CML (group II) at 11 hematology centers in Nagasaki prefecture, Japan, from December 2001 to July 2005 and analyzed the molecular responses. Cytopenia, fluid retention, and skin rash were major adverse events, along with elevation in creatine phosphokinase levels. With a follow-up of approximately 3.5 years, imatinib treatment led to 88.7% overall survival (OS) and 85.2% progression-free survival (PFS) rates for group I, and 79.8% OS and 76.6% PFS rates for group II; the rates were not significantly different despite a lower average imatinib dose in group II. The rates of complete cytogenetic response at 30 months and major molecular response at 24 months were 86.1% and 62.5%, respectively, in group I, and 77.9% and 58.3% in group II; the rates were not significantly different. As has been reported by other groups, these results demonstrate that imatinib treatment can provide excellent clinical and molecular effects for not only newly diagnosed but also previously treated CML patients in practical settings that cover a wider variety of patients than clinical trials.