Abstract
TRICYCLIC antidepressants are commonly used orally in the therapy of chronic pain, such as diabetic neuropathy, 1,2 postherpetic neuralgia, 3 migraine, 4 fibromyalgia and myofascial pain, 5 chronic orofacial pain, 6 central pain, and peripheral neuropathy of different etiology. 7 Among them, amitriptyline has become a mainstay for the treatment of neuropathic pain, which is thought to be caused by an abnormal spontaneous high-frequency ectopic discharge. 8 Amitriptyline was shown to block various voltage-gated ion channels, for example, Na+, K+, and Ca+channels. 9–11 Furthermore, it inhibits the reuptake of serotonin and norepinephrine 12; blocks α2-adrenergic, nicotinic, muscarinic cholinergic, N -methyl-d-aspartate, and histaminergic receptors 13–17; and interacts with opioid and adenosine receptors. 18,19 Overall, the site of action of amitriptyline is probably both central and peripheral, 20 with a therapeutic plasma concentration of 0.3–0.8 μm. 21 One of the interesting features of amitriptyline is an additional Na+channel blockade (termed as use-dependent or phasic block) at high-frequency stimulation. For example, amitriptyline increased Na+channel blockade in isolated rabbit atrial and myocardial myocytes when stimulated at a high frequency 22; the same held true for voltage-gated Na+currents in bovine adrenal chromaffin cells and neonatal dorsal root ganglion cells. 9 This phenomenon of use dependency is also found with clinically used local anesthetics. Although in numerous reports amitriptyline was shown to effectively decrease the pain sensation, especially for thermal hyperalgesia in rats by various routes of administration (per oral, intrathecal, peritoneal), 23 or when combined with opioids or clonidine, 18,24 the exact mechanism of diminishing the pain sensation is not known. To date, amitriptyline has not been reported as a single agent for peripheral nerve blockade. We therefore compared the effectiveness of amitriptyline and bupivacaine for sciatic nerve blockade in rats. To extend our in vivo studies, we also extended former work on the potency and use-dependent blockade of amitriptyline 9 by investigating its voltage-dependent blockade and comparing it to bupivacaine during identical conditions in cultured neuronal cells.