We were unable to assess phasic block of C fibers in this preparation due to the relative large stimulus requirements and small amplitude of the C fiber signal in rat sciatic nerves, and to the tendency of compound C fiber signals to increase in amplitude (in the absence of drugs) with repetitive stimulation (19,20).
A distinct separation between concentrations of clonidine or guanfacine inhibiting motor and sensory fibers (unlike the case for local anesthetics, including bupivacaine) would be consistent with the relatively greater potency at inhibition of C fibers compared to Aα fibers which we report for clonidine and guanfacine. The absence of motor block in clinical and animal studies with clonidine argues against our explanation of the analgesia which follows epidural or spinal administration of α2-adrenergic agonists. However, side effects of epidurally administered clonidine (e.g., somnolence and hypotension) have limited its dosage in patients, preventing use of higher doses which might have produced motor block as significant Aα fiber inhibition was achieved (3,9,13,23). In humans, the concentration of clonidine in cerebrospinal fluid peaks at 4.5 μM after a large (700 μg) epidural dose (Dr. James Eisenach, Winston-Salem, NC, personal communication). We note that reduced concentrations of bupivacaine provide intense analgesia without producing perceptible motor block in patients (e.g., in parturients receiving epidural analgesia) despite the absence, in careful experimental studies, of a tendency to inhibit C fibers preferentially (24). If α2-agonists exhibit the same relationship between concentrations inhibiting nerve excitability (micromolar range) and impulse conduction (millimolar range) as do procaine and lidocaine (25-27), cerebrospinal fluid concentrations after epidural drug administration may be more than sufficient to perturb normal patterns of impulse activity.
The analgesic efficacy of oral and intravenous clonidine also argues against our explanation for α2-adrenergic agonist-induced analgesia. Is this evidence that all analgesia produced by α2-adrenergic receptor agonists results from drug binding to specific α2-adrenergic receptors, rather than from binding to and inhibition of (presumably) Na+ channels, even when drugs are applied regionally near nerves? We suspect not, but recognize that studies in which specific antagonists are present will be required to resolve the issue. We note that there are a number of compounds whose mechanism of action may change depending on their site of injection. Meperidine provides analgesia when administered systemically by binding to opioid receptors in the brain and spinal cord. When administered as a spinal anesthetic, meperidine produces sensory and motor block resembling that produced by local anesthetics (28). Meperidine may also provide greater analgesia than saline when used during intravenous regional anesthesia (29). Moreover, lidocaine, which is thought to produce regional anesthesia by inhibiting voltage-gated Na+ channels, relieves neuropathic pain and reduces the requirements for general anesthetic agents in humans when administered intravenously (30,31). Although the mechanism of these latter two effects remains unclear, low systemic concentrations of lidocaine and procaine profoundly reduce the excitability of central and peripheral neurons (26,27).
Finally, substance P antagonists, which initially were thought to produce spinal analgesia by specifically inhibiting binding of substance P to its receptor, produce reversible inhibition of impulse conduction along peripheral nerve axons similar to that produced by local anesthetics (32). In short, α2-adrenergic agonists, like other drug classes, may have multiple possible mechanisms of action, depending on the concentration and the site of administration.
Guanfacine demonstrated greater potency than clonidine at both tonic and phasic block. It may be important that at any given degree of tonic block, guanfacine produced greater phasic block than clonidine. Although a relationship between phasic block and clinical analgesia (from local anesthetics) has not been established, increased inhibition during trains of impulses remains an attractive explanation for the intense analgesia provided by “subanesthetic” doses of bupivacaine, as, for example, during labor (24). Using that argument, one would predict that guanfacine would be a better agent for clinical analgesia than clonidine. However, studies comparing the antinociceptive potency of clonidine and guanfacine have yielded conflicting data (7,33).
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