Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current

Abstract

Background: The current study was designed to test the hypothesis that the increased duration of analgesia caused by adding dexmedetomidine to local anesthetic results from blockade of the hyperpolarization-activated cation (I(h)) current.

Methods: In this randomized, blinded, controlled study, the analgesic effects of peripheral nerve blocks using 0.5% ropivacaine alone or 0.5% ropivacaine plus dexmedetomidine (34 μM or 6 μg/kg) were assessed with or without the pretreatment of α(1)- and α(2)-adrenoceptor antagonists (prazosin and idazoxan, respectively) and antagonists and agonists of the I(h) current (ZD 7288 and forskolin, respectively). Sciatic nerve blocks were performed, and analgesia was measured by paw withdrawal latency to a thermal stimulus every 30 min for 300 min postblock.

Results: The analgesic effect of dexmedetomidine added to ropivacaine was not reversed by either prazosin or idazoxan. There were no additive or attenuated effects from the pretreatment with ZD 7288 (I(h) current blocker) compared with dexmedetomidine added to ropivacaine. When forskolin was administered as a pretreatment to ropivacaine plus dexmedetomidine, there were statistically significant reductions in duration of analgesia at time points 90-180 min (P < 0.0001 for each individual comparison). The duration of blockade for the forskolin (768 μM) followed by ropivacaine plus dexmedetomidine group mirrored the pattern of the ropivacaine alone group, thereby implying a reversal effect.

Conclusion: Dexmedetomidine added to ropivacaine caused approximately a 75% increase in the duration of analgesia, which was reversed by pretreatment with an I(h) current enhancer. The analgesic effect of dexmedetomidine was not reversed by an α(2)-adrenoceptor antagonist.

Figure 1. Prazosin and Idazoxan Did Not Attenuate the Analgesic Effects of Perineural Dexmedetomidine Added to Ropivacaine

Each rat received a pretreatment perineural injection followed by a second injection 10 min later. The duration of sensory blockade was measured by assessing paw withdrawal latency (PWL) to a heat stimulus every 30 min following the nerve block with a maximum response of 15 s. All of the groups containing dexmedetomidine plus ropivacaine had a longer duration of sensory blockade when compared with ropivacaine alone. Groups are noted in the upper right by the “Pretreatment/Second Injection.” ∝ = 0.00833 * indicates a significant difference for all three DEX groups when compared with the Saline/Ropiv control group. + indicates Saline/DEX+Ropiv and Prazosin/DEX+Ropiv are each significantly different from the Saline/Ropiv control group. # indicates Prazosin/DEX+Ropiv significantly differs from both Idazoxan/DEX+Ropiv and the Saline/Ropiv control group. BL = baseline; DEX = dexmedetomidine; Ropiv = ropivacaine

Figure 2. The I_h Blocker ZD 7288 Did Not Increase the Duration of Dexmedetomidine-Mediated Analgesia

The duration of the sciatic nerve block was measured by paw withdrawal latency (PWL) to a thermal stimulus every 30 min. Both ZD 7288 and dexmedetomidine increased the duration of sensory blockade when compared with the Saline/Ropivacaine control group. There was no additive effect when both ZD 7288 and dexmedetomidine were coadministered with ropivacaine. Groups are noted in the upper right by the “Pretreatment/Second Injection.” ∝ = 0.00833 * indicates the Saline/Ropiv control group is significantly different from the other three groups. At 150 min, there is also a significant difference between Saline/DEX+Ropiv and ZD 7288/Ropiv. # indicates Saline/DEX+Ropiv and ZD 7288/Ropiv are each significantly different from the Saline/Ropiv control group. BL = baseline; DEX = dexmedetomidine; Ropiv = ropivacaine

Figure 3. Forskolin Attenuated the Analgesic Effects of Dexmedetomidine Added to Ropivacaine

When the I_h agonist, forskolin, was given as a pretreatment to the dexmedetomidine plus ropivacaine combination, the duration of analgesia mirrored that of ropivacaine alone and was significantly different than the Saline/DEX+Ropiv group. Forskolin pretreatment also attenuated the analgesic effects of ropivacaine alone, as noted by the differences between the Forskolin/Ropiv and Saline/Ropiv groups. Groups are noted in the upper right by the “Pretreatment/Second Injection.” ∝ = 0.00833 # indicates that the Forskolin/Ropiv group is significantly different from the other three groups. + indicates that the Saline/Ropiv control group is significantly different from the other three groups. Forskolin/Ropiv is also significantly different from the remaining two groups. * indicates that the Saline/DEX+Ropiv group is significantly different from the other three groups. At 120 min, there is also a significant difference between the two Forskolin groups. BL = baseline; DEX = dexmedetomidine; PWL = paw withdrawal latency; Ropiv = ropivacaine