Ketamine supresses REM sleep and markedly increases EEG gamma oscillations in the Wistar Kyoto rat model of treatment-resistant depression.

Wistar-Kyoto (WKY) rats exhibit depression-like characteristics and decreased sensitivity to monoamine-based antidepressants, making them a suitable model of treatment-resistant depression (TRD). Ketamine has emerged recently as a rapidly acting antidepressant with high efficacy in TRD. Our aim was to determine whether subanaesthetic doses of ketamine can correct sleep and electroencephalogram (EEG) alterations in WKY rats and whether any ketamine-induced changes differentially affect WKY rats compared to Sprague-Dawley (SD) rats. Thus, we surgically implanted 8 SD and 8 WKY adult male rats with telemetry transmitters and recorded their EEG, electromyogram, and locomotor activity after vehicle or ketamine (3, 5 or 10 mg/kg, s.c.) treatment. We also monitored the plasma concentration of ketamine and its metabolites, norketamine and hydroxynorketamine in satellite animals. We found that WKY rats have an increased amount of rapid eye movement (REM) sleep, fragmented sleep-wake pattern, and increased EEG delta power during non-REM sleep compared to SD rats. Ketamine suppressed REM sleep and increased EEG gamma power during wakefulness in both strains, but the gamma increase was almost twice as large in WKY rats than in SD rats. Ketamine also increased beta oscillations, but only in WKY rats. These differences in sleep and EEG are unlikely to be caused by dissimilarities in ketamine metabolism as the plasma concentrations of ketamine and its metabolites were similar in both strains. Our data suggest an enhanced antidepressant-like response to ketamine in WKY rats, and further support the predictive validity of acute REM sleep suppression as a measure of antidepressant responsiveness.

Preclinical Neuropathic Pain Assessment; the Importance of Translatability and Bidirectional Research.

For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of development of new analgesics for neuropathic pain has been the mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. Despite continuous forward translation failures across diverse mechanisms, reflexive quantitative sensory testing remains the primary assessment endpoint for neuropathic pain and analgesia in animals. Restricting preclinical evaluation of pain and analgesia to exclusively reflexive outcomes is over simplified and can be argued not clinically relevant due to the continued lack of forward translation and failures in the clinic. The key to developing new analgesic treatments for neuropathic pain therefore lies in the development of clinically relevant endpoints that can translate preclinical animal results to human clinical trials. In this review we discuss this mismatch of primary neuropathic pain assessment endpoints, together with clinical and preclinical evidence that supports how bidirectional research is helping to validate new clinically relevant neuropathic pain assessment endpoints. Ethological behavioral endpoints such as burrowing and facial grimacing and objective measures such as electroencephalography provide improved translatability potential together with currently used quantitative sensory testing endpoints. By tailoring objective and subjective measures of neuropathic pain the translatability of new medicines for patients suffering with neuropathic pain will hopefully be improved.

Utility of the digital rectal examination in the evaluation of undifferentiated abdominal pain.

OBJECTIVE: The digital rectal examination (DRE) is commonly recommended in the evaluation of individuals with undifferentiated abdominal pain (UAP) despite negligible evidence. We aimed to determine its clinical utility. METHODS: We prospectively enrolled 893 UAP subjects in an observational, convenience sample study at our urban, academic emergency department. Exclusion criteria were age younger than 18 years, vaginal or rectal bleeding, pregnancy, and primarily flank pain or vaginal complaint. Data forms were completed before laboratory testing, imaging, or other diagnostic maneuvers; and structured telephone and chart follow-up was performed. Physicians were asked to document DRE findings contemporaneously as well as their perception of the DRE's diagnostic impact. Final diagnosis in each case was compared with DRE result. RESULTS: Five hundred thirty-eight of 893 (60%) subjects had a DRE performed at the discretion of the examining physician. The DRE was classified as "not useful" in 494 of 538 (92%). In the remaining 44 subjects, physicians reported having their differential diagnosis influenced by the DRE. Seventeen of 538 (3%; 0.95 confidence interval, 1.9%-5.0%) were diagnostically helped, and 12 of 538 (2%; 0.95 confidence interval, 1.3%-3.9%) were diagnostically harmed. Eleven of 538 (2%) were lost to final follow-up. Sensitivity analysis indicates that unless all 11 had diagnostically helpful DREs, the DRE was statistically as likely to be harmful as helpful. CONCLUSION: Differential diagnosis was unaffected in most subjects undergoing DRE, and it appears as likely to be harmful as helpful in predicting final diagnosis. Given the discomfort and minimal predictive value of the DRE in this setting, highly selective use seems reasonable.