Delayed Goblet Cell Hyperplasia, Acetylcholine Receptor Expression, and Worm Expulsion in SMC-Specific IL-4Rα–Deficient Mice

Interleukin 4 receptor α (IL-4Rα) is essential for effective clearance of gastrointestinal nematode infections. Smooth muscle cells are considered to play a role in the type 2 immune response–driven expulsion of gastrointestinal nematodes. Previous studies have shown in vitro that signal transducer and activator of transcription 6 signaling in response to parasitic nematode infection significantly increases smooth muscle cell contractility. Inhibition of the IL-4Rα pathway inhibits this response. How this response manifests itself in vivo is unknown. In this study, smooth muscle cell IL-4Rα–deficient mice (SM-MHC(Cre)IL-4Rα(−/lox)) were generated and characterized to uncover any role for IL-4/IL-13 in this non–immune cell type in response to Nippostrongylus brasiliensis infection. IL-4Rα was absent from α-actin–positive smooth muscle cells, while other cell types showed normal IL-4Rα expression, thus demonstrating efficient cell-type–specific deletion of the IL-4Rα gene. N. brasiliensis–infected SM-MHC(Cre)IL-4Rα(−/lox) mice showed delayed ability to resolve infection with significantly prolonged fecal egg recovery and delayed worm expulsion. The delayed expulsion was related to a delayed intestinal goblet cell hyperplasia, reduced T helper 2 cytokine production in the mesenteric lymph node, and reduced M3 muscarinic receptor expression during infection. Together, these results demonstrate that in vivo IL-4Rα–responsive smooth muscle cells are beneficial for N. brasiliensis expulsion by coordinating T helper 2 cytokine responses, goblet hyperplasia, and acetylcholine responsiveness, which drive smooth muscle cell contractions

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

The 5-HT(4) receptor agonist, tegaserod, is a potent 5-HT(2B) receptor antagonist in vitro and in vivo

1. Tegaserod (Zelnorm®) is a potent 5-hydroxytryptamine(4) (5-HT(4)) receptor agonist with clinical efficacy in disorders associated with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5-HT(2) receptors, and compared its potency in this respect to its 5-HT(4) receptor agonist activity. 2. Tegaserod had significant binding affinity for human recombinant 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors (pK(i)=7.5, 8.4 and 7.0, respectively). The 5-HT(2B) receptor-binding affinity of tegaserod was identical to that at human recombinant 5-HT(4(c)) receptors (mean pK(i)=8.4) in human embryonic kidney-293 (HEK-293) cells stably transfected with the human 5-HT(4(c)) receptor. 3. Tegaserod (0.1–3 μM) inhibited 5-HT-mediated contraction of the rat isolated stomach fundus potently (pA(2)=8.3), consistent with 5-HT(2B) receptor antagonist activity. Tegaserod produced, with similar potency, an elevation of adenosine 3′,5′ cyclic monophosphate in HEK-293 cells stably transfected with the human 5-HT(4(c)) receptor (mean pEC(50)=8.6), as well as 5-HT(4) receptor-mediated relaxation of the rat isolated oesophagus (mean pEC(50)=8.2) and contraction of the guinea-pig isolated colon (mean pEC(50)=8.3). 4. Following subcutaneous administration, tegaserod (0.3 or 1 mg kg(−1)) inhibited contractions of the stomach fundus in anaesthetized rats in response to intravenous dosing of α-methyl 5-HT (0.03 mg kg(−1)) and BW 723C86 (0.3 mg kg(−1)), selective 5-HT(2B) receptor agonists. At similar doses, tegaserod (1 and 3 mg kg(−1) subcutaneously) evoked a 5-HT(4) receptor-mediated increase in colonic transit in conscious guinea-pigs. 5. The data from this study indicate that tegaserod antagonizes 5-HT(2B) receptors at concentrations similar to those that activate 5-HT(4) receptors. It remains to be determined whether this 5-HT(2B) receptor antagonist activity of tegaserod contributes to its clinical profile