Interaction between midazolam and serotonin in spinally mediated antinociception in rats

Intrathecal administration of serotonin (5-HT) is antinociceptive through the involvement of spinal cord gamma-aminobutyric acid (GABA) receptors. Therefore, 5-HT would interact with the GABA agonist, midazolam, which is well known to exert spinally mediated antinociception in the spinal cord. The present study investigated the antinociceptive interaction between spinally administered 5-HT and midazolam, using two different rat nociceptive models.

Sprague-Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and paw flinches induced by formalin injection after the intrathecal administration of midazolam or 5-HT, or the midazolam/ HT combination. The effects of the combination were tested by isobolographic analysis, using the combination of each 1, 1/2, 1/4, 1/8, and 1/16 of the 50% effective dose (ED50). The total fractional dose was calculated. Behavioral side effects were also examined.

5-HT alone and midazolam alone both showed dose-dependent antinociception in both the tail flick test and the formalin test. The ED50 of the combination was not different from the calculated additive value either in the tail flick test or in phase 2 of the formalin test, but it was significantly smaller than the calculated additive value in phase 1 of the formalin test. The total fractional dose value was 0.90 in the tail flick test, 0.093 in phase 1 of the formalin test, and 1.38 in phase 2 of the formalin test. The agitation, allodynia, or motor disturbance observed with either agent alone was not seen with the combination treatment.

The antinociceptive effects of intrathecal midazolam and 5-HT were additive on thermal acute and inflammatory facilitated stimuli, and synergistic on inflammatory acute stimulation.