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.