This study used concordant behavioral and electrophysiological approaches to examine the actions of the prototypic kappa opioid receptor agonist U69593 in the rostral ventromedial medulla (RVM). In vitro whole-cell voltage clamp recordings indicated that bath application of U69593 produced outward currents in primary cells in the RVM. In secondary cells, which comprised 80% of the population, U69593 produced a concentration-dependent and norbinaltorphimine (norBNI)-reversible inhibition of evoked excitatory postsynaptic currents (EPSCs) in the absence of any postsynaptic effect. U69593 also decreased the frequency, but not the amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in secondary cells. The inhibition of excitatory inputs to secondary cells would be consonant with disinhibition of primary cells and the production of antinociception. Consistent with this expectation, the activation of kappa opioid receptors in the RVM by microinjection of U69593 produced a dose-dependent increase in paw-withdrawal latency that was antagonized by norBNI. Furthermore, microinjection of norBNI in the RVM antagonized the increases in paw-withdrawal latency and hot-plate latency produced by systemically-administered U69593. In contrast, microinjection of norBNI in the RVM did not antagonize the increase in tail-flick latency produced by systemically-administered U69593. Also, microinjection of U69593 in the RVM did not increase tail-flick latency. The highly test-dependent nature of U69593's effects suggests that the mechanisms by which neurons in the RVM modulate thermal nociceptive responses evoked from the tail and hindpaw are not uniform. Collectively, these data suggest that the RVM is a primary site of action for the antinociceptive actions of kappa opioid receptor agonists and that the mechanism most likely involves a presynaptic inhibition of excitatory inputs to secondary cells. Thus, disinhibition of pain inhibitory neurons in the RVM is likely to be a common mechanism by which opioid receptor agonists produce antinociception, whether by the direct inhibition of inhibitory secondary cells, as in the case of mu opioid receptor agonists, or by a reduction in the excitatory drive to these neurons, as in the case of kappa opioid receptor agonists.
An HRE is associated with a high prevalence of TID in patients without other significant perfusion defects, possibly as a result of global subendocardial ischemia induced by the HRE.
Background and Purpose-Carotid intima-media thickness (CIMT) is associated with systemic atherosclerosis and cardioembolic conditions and predicts the risk of recurrent strokes. We sought to establish the relationship between CIMT and cardiovascular sources of embolus (CSE) on transesophageal echocardiography (TEE) and hypothesized that a noninvasive strategy of CIMT assessment and transthoracic echocardiography bubble study would identify patients with ischemic stroke or transient ischemic attack in whom TEE would provide little incremental diagnostic yield. Methods-In 180 patients with ischemic stroke or transient ischemic attack of undetermined origin referred for TEE, we prospectively performed CIMT measurement/plaque screen (Phase 1, nϭ96) or CIMT measurement/plaque screen and transthoracic echocardiography bubble study (Phase 2, nϭ84) before TEE. Phase 1 results were used to construct receiver operating characteristic curves to demonstrate the ability of CIMT to detect CSE on TEE and to identify the optimal CIMT cutoff value for prospective strategy testing (Phase 2). Results-In Phase 1, CIMT was found to correlate with TEE markers of aortic atherosclerosis, including complex aortic plaques, and combined CSE. The optimal CIMT cutoff for detection of CSE on TEE was 0.78 mm. In Phase 2, a positive noninvasive strategy test (CIMT Ն0.78 mm, ϩcarotid plaque, and/or a positive transthoracic echocardiography bubble study) was present in 61%. The prevalence of CSE on TEE was significantly higher among those with a positive compared with a negative noninvasive strategy test (65% versus 9%, PϽ0.001), and this strategy had a sensitivity of 92% and a negative predictive value of 91% for the detection of any CSE on TEE. Conclusion-In patients with stroke or transient ischemic attack of undetermined origin, a noninvasive strategy of CIMT assessment/plaque screen and transthoracic echocardiography bubble study can identify patients in whom further invasive evaluation with TEE will be of low diagnostic yield.
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