A translational study of the effects of ketamine and pregabalin on temporal summation of experimental pain.

BACKGROUND AND OBJECTIVES: Central sensitization is often seen in chronic pain. A relevant and potent mechanism of central sensitization is the central integration of nociceptive impulses. Temporal summation in humans and the wind-up process in animals share common features of central integration. This preclinical and clinical translational study investigated the effect of ketamine and pregabalin on temporal summation (TS) and wind-up of wide dynamic range (WDR) neurons of nociceptive electrical stimuli in healthy volunteers and rats. METHODS: This 3-way crossover study included healthy male volunteers (n = 18) receiving 3 doses of 300 mg pregabalin (orally) over 2 days, ketamine (intravenous loading dose 0.5 mg/kg followed by 9 µg/kg per minute for 20 mins) on the first day, or placebo. The pain detection thresholds to repetitive electrical cutaneous and suprathreshold responses stimulation were assessed.In male Sprague-Dawley rats (n = 30), WDR neuron recordings after electrical stimulation were obtained before and after 15 minutes of intravenous infusion pregabalin (0.127, 0.42, and 1.27 mg/kg per minute) and ketamine (0.006, 0.02, 0.06, and 0.2 mg/kg per minute). RESULTS: In the human study, ketamine compared with placebo significantly increased the TS pain detection threshold (P < 0.001) and significantly reduced suprathreshold pain responses (P < 0.001). In rats, the highest dose of ketamine significantly inhibited the wind-up response of the WDR neurons (P = 0.014). Pregabalin affected neither of the parameters in TS and WDR responses. CONCLUSIONS: It was shown that TS shares common features with wind-up of WDR neurons and that pregabalin does not affect this component of central sensitization.

In vitro and in vivo SAR of pyrido[3,4-d]pyramid-4-ylamine based mGluR1 antagonists.

The SAR of a series of novel pyrido[3,4-d]pyramid-4-ylamine mGluR1 antagonists is described. The multiple of the unbound K(i) in cerebrospinal fluid necessary to give morphine like analgesic effects in an electromyograph pinch model in rodents is determined and the effect of structure on CNS penetration examined.

Efficacy of spinal cord stimulation for neuropathic pain: assessment by abstinence.

Assessment of the efficacy of spinal cord stimulation (SCS) against neuropathic pain remains problematic. Some patients may underestimate this, as revealed by their reaction to stimulator malfunction. This study investigated whether abstinence from SCS would provide an indication of its effectiveness. Patients were invited to complete two brief questionnaires each day for 50 days including two periods of 14 days without stimulation. Pain level, sleep quality, activity level and drug intake were recorded. Of 75 patients thought to be using their stimulators, 12 did not respond to the invitation, eight had unresolved technical problems and one no longer needed SCS. Of the 54 remaining, 10 did not wish to be without SCS and 15 declined without giving a reason. Thus 29 agreed to take part but three then dropped out through illness and questionnaires were not received from 10. Ten returned completed questionnaires but failed to follow the protocol; five of these were unable to leave their stimulators off. Only six took part correctly. Twenty of the 29 had received a preliminary explanatory home visit and for nine this was done by telephone. The former produced a considerably higher yield. All six who completed the study correctly had statistically significantly lower pain scores during stimulation. Four had improved sleep but only one reduced his medication and none of the six increased their activity levels. Correlation with previous clinical assessments is discussed. It is concluded that the abstinence principle might provide a useful tool but its power is very methodology-dependent.