Low-dose atropine amplifies cardiac vagal modulation and increases dynamic baroreflex function in humans.

It has been previously known that low-dose atropine (LDA) enhances vagal outflow to the heart. To demonstrate the importance of vagal cardiac modulation in arterial blood pressure (ABP) stability, we evaluated the effect of vagal cardiac stimulation with administration of LDA on ABP fluctuation during dynamic hypertensive and hypotensive stimuli. We assessed changes in RR interval (RRI), ABP, power spectral densities of heart rate variability (HRV) and ABP variability, and spontaneous baroreflex sensitivity (BRS) in 16 healthy volunteers before and after administration of LDA (2 microg/kg). Transient hypertension was induced by phenylephrine (2 microg/kg), whereas hypotension was induced by bilateral thigh cuff deflation after a 3-min suprasystolic occlusion. LDA elicited bradycardia and significantly increased high-frequency (HF, 0.15-0.4 Hz) power of HRV and spontaneous BRS, as determined by transfer function analysis. The increase in systolic blood pressure (SBP) after phenylephrine administration was significantly attenuated by LDA (16+/-2 to 11+/-3 mmHg, P<0.005) and was associated with the augmented reflex bradycardia, whereas the decrease in SBP after cuff deflation was not affected (14+/-5 to 13+/-5 mmHg) with the augmented reflex tachycardia. Increases of HF HRV were correlated significantly and negatively with the increased SBP induced by phenylephrine before and after LDA (r=-0.502, P<0.05). These data suggest that the increased vagal cardiac function induced by LDA augments HR buffering effects, and is important in minimizing arterial pressure fluctuation during dynamic hypertensive stimuli.

Morphine can enhance the antiallodynic effect of intrathecal R-PIA in rats with nerve ligation injury.

Nerve ligation injury may produce a tactile allodynia. Intrathecal adenosine receptor agonists or morphine have an antiallodynic effect. In this study, we examined the effect of intrathecal morphine on the antiallodynic state induced by the adenosine A1 receptor agonist, N(6)-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA), in a rat model of nerve ligation injury. Rats were prepared with ligation of left L5-6 spinal nerves and intrathecal catheter implantation. Tactile allodynia was measured by applying von Frey filaments to the lesioned hindpaw. Thresholds for withdrawal response were assessed. Morphine and R-PIA were administered to obtain the dose-response curve and the 50% effective dose (ED(50)). Fractions of ED(50)s were administered concurrently to establish the ED(50) of the drug combination. The drug interaction was analyzed using the isobolographic method. Intrathecal 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1 receptor antagonist, and naloxone were administered to examine the reversal of the antiallodynic effect. Side effects were also observed. Intrathecal morphine and R-PIA and their combination produced a dose-dependent antagonism without severe side effects. Intrathecal morphine synergistically enhanced the antiallodynic effect of R-PIA when coadministered. Intrathecal naloxone and DPCPX reversed the maximal antiallodynic effect in the combination group. These results suggest that activation of mu-opioid and A1 receptors at the spinal level is required for the synergistic interaction on tactile allodynia.