Oral doses of dextromethorphan (DM), a common cough suppressant and N-methyl-D-aspartate (NMDA) receptor antagonist, and their vehicle control were given on a double-blind basis to normal volunteer human subjects who rated intensities of first and second pain in response to repeated painful electric shocks and repeated 52 degrees C heat pulses. Doses of 30 and 45 mg, but not 15 mg, were effective in attenuating temporal summation of second pain, a psychophysical correlate of temporal summation of C afferent-mediated responses of dorsal horn nociceptive neurons, termed 'wind-up'. By contrast, neither first nor second pain evoked by the first stimulus in a train of stimuli were affected by any of these doses of DM. These results further confirm temporal summation of second pain as a psychophysical correlate of wind-up by providing evidence that DM selectively reduces temporal summation of second pain, as has been shown for wind-up.

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N-Methyl-D-aspartate (NMDA) receptor antagonists have been repeatedly shown to attenuate the development of opiate tolerance and dependence in rodents. In the present experiments, continuous subcutaneous infusion of either MK-801 (0.01 mg/kg/h but not 0.005 mg/kg/h) or DM (0.133, 0.67 and 1.33 mg/kg/h) reliably prolonged the antinociceptive effect of continuous subcutaneous infusion of morphine sulfate (2.0 mg/kg/h), indicating attenuation of the development of morphine tolerance. Furthermore, this prolonged antinociception was completely reversible by naloxone (10 mg/kg, i.p.). Doses of MK-801 and DM that were equipotent in attenuating morphine tolerance (0.01 mg/kg/h and 1.33 mg/kg/h, respectively) revealed different profiles of effects, however, on locomotor activity and naloxone-precipitated abstinence/withdrawal symptoms. With regard to locomotor activity, rats having received continuous (48 h) subcutaneous infusion of morphine sulfate and MK-801, but not rats having received morphine sulfate and DM, displayed a reliable and striking increase in locomotor activity as compared with rats having received morphine alone. With regard to naloxone-precipitated withdrawal symptoms, continuous (48 h) subcutaneous co-infusion of either MK-801 (0.01 mg/kg/h) or DM (1.33 mg/kg/h) with morphine attenuated naloxone-precipitated hyperalgesia as compared with rats infused with morphine alone. MK-801 (0.01 mg/kg/h) was more effective than DM (0.133, 0.67, or 1.33 mg/kg/h), however, in reducing other naloxone-precipitated withdrawal symptoms (teeth chattering, jumping and wet dog shakes). The effects of MK-801 on all withdrawal symptoms were confounded, however, by the appearance of flaccidity following naloxone administration to rats having received MK-801 and morphine. These results extend previous observations by showing that the prolonged antinociception observed following co-administration of morphine and an NMDA antagonist is completely naloxone-reversible, supporting the notion that this antinociception reflects prolongation of an opioid receptor-mediated effect. The different profiles of side effects associated with MK-801 and DM, however, suggest that (1) attenuation of naloxone-precipitated withdrawal symptoms by MK-801 may be an artifact of toxicity, and (2) DM may prove clinically useful for the prevention of morphine tolerance, given its lack of observable side effects when administered concurrently with morphine to rodents.

In the United States 258,000 people were injured in 2004 in motor vehicle accidents that were caused by drivers under the influence of alcohol. The majority of these drivers were binge drinkers, most notably young people who tend to drink heavily during the weekends, but rarely drink alcohol during the week. Since a large proportion of the injuries involved head injuries, the present study aimed at investigating the influence of binge alcohol drinking on mild traumatic brain injury (mTBI) in an animal model. Mice had access to 0%, 7.5%, 15%, or 30% alcohol solutions for 48 consecutive hours once a week for 4 weeks as the sole source of fluids (the remaining time they drank water). Three experiments were done. For the first one (alcohol-mTBI-alcohol) the animals were subjected to a controlled mTBI injury by applying a closed-head weight drop, or a sham procedure. After the mTBI/sham-mTBI the animals got alcohol and /water for the same regimen for 4 additional weeks. In the second experiment (alcohol only) after the 4 weeks of drinking blood samples were collected, at the same time as the animals that underwent sham-mTBI or mTBI procedures. In the third experiment (mTBI-alcohol) the mice were subjected to mTBI/sham-mTBI without any treatment, and after mTBI they had alcohol for 4 weeks in the same regimen as in the previous experiments. At the end of the pharmacological treatment all animals were assessed using different behavioral tests. mTBI mice exhibited lower memory ability in the Y-maze, higher anxiety in the elevated plus maze, and lower retention in the passive avoidance test than sham-mTBI animals. Alcohol reversed these effects at all doses. The results suggest that alcohol drinking before trauma might have a protective effect on recovery from brain trauma, but not if consumed after the trauma.