New higher precision measurements of the hyperfine Zeeman transitions in the ground state of muonium have been performed with use of the high-stopping-density surface \i + beam at the Clinton P 0 Anderson Meson Physics Facility. The results are Ay = 4 463-302.88(16) kHz (0.036 ppm) and n^/np^ 3.183 3461(11) (0.36 ppm). The current theoretical value of Ay agrees well with experiment within the 0.77-ppm error of Ay t^eor , which is due principally to inaccuracy in evaluation of the nonrecoil radiative correction term. The most precise current value of m n /m e is obtained from our value of \ij\x p ,
Opioid receptors in the gastrointestinal (GI) tract mediate the effects of endogenous opioid peptides and exogenously administered opioid analgesics, on a variety of physiological functions associated with motility, secretion and visceral pain. The studies reviewed or reported here describe a range of in vivo activities of opioid receptor antagonists upon GI function in rodents, focusing on mu receptors. Naloxone, and the peripherally acting mu-opioid receptor antagonists alvimopan and methylnaltrexone, reverse morphine-induced inhibition of GI transit in mice and rats, and morphine- or loperamide-induced inhibition of castor oil-induced diarrhoea in mice. At doses producing maximal reversal of morphine-induced effects upon GI transit, only the central nervous system (CNS) penetrant antagonist naloxone was able to reverse morphine-induced analgesia. Both central and peripheral opioid antagonists may affect GI function and/or visceromotor sensitivity in the absence of exogenous opioid analgesics, suggesting a constitutive role for endogenous opioid peptides in the control of GI physiology. Furthermore, in contrast to naloxone, alvimopan does not produce hypersensitivity to the visceromotor response induced by nociceptive levels of colorectal distension in a rodent model of post-inflammatory colonic hypersensitivity, suggesting that in the periphery endogenous mu-opioid receptor-mediated mechanisms do not regulate colonic sensitivity. The data support the hypothesis that peripherally acting opioid antagonists may be able to selectively block opioid receptors in the GI tract, thereby preserving normal GI physiology, while not blocking the effects of endogenous opioid peptides or exogenous opioid analgesics in the CNS. These findings suggest that the primary sites of action of mu-opioid agonists with respect to inhibition of GI function are in the periphery, whereas analgesic activity resides primarily in the CNS.
Following our earlier observations that the tachykinin NK1 receptor antagonist CP‐99,994 is an effective anti‐emetic in ferrets, we have examined the anti‐emetic effects of a more potent and novel NK1 receptor antagonist, GR203040, against various emetic stimuli in the ferret, dog and house musk shrew (Suncus murinus).
In ferrets, GR203040 (0.1 mg kg−1 s.c. or i.v.) is effective against emesis induced by radiation, cisplatin, cyclophosphamide, copper sulphate, ipecacuanha or morphine.
In animals in which emesis had been established with cisplatin, GR203040 (1 mg kg−1 s.c.) was fully effective as an interventional treatment. No further emesis was seen in animals treated with GR203040 whilst saline‐treated animals continued to vomit.
GR203040 (0.1 mg kg−1 s.c.) retains anti‐emetic efficacy in the ferret, even when given as a 6 h pretreatment, indicating that this compound has a long duration of action. The compound is also effective orally at the same dose, when given as a 90 min pretreatment.
GR203040 (0.1 mg kg−1 i.v.) is fully effective against ipecacuanha‐induced emesis in the dog.
GR203040 is effective against motion‐and cisplatin‐induced emesis in Suncus murinus. These effects were seen at doses an order of magnitude greater than those shown to be effective against cisplatin in the ferret.
In conclusion, GR203040 is a novel anti‐emetic agent, and the broad spectrum of anti‐emetic activity, together with activity observed in three species, suggests that this compound is worthy of clinical investigation.
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