Local anesthetic effects of cocaethylene and isopropylcocaine on rat peripheral nerves

Abstract

Cocaethylene is a naturally occurring cocaine derivative that has been used as a tool in both clinical studies of cocaine reward and as a potential model compound for agonist substitution therapy in cocaine dependence. It is equipotent to cocaine at inhibiting dopamine uptake in-vitro and in-vivo. Because it has been reported that local anesthetic properties may influence the reinforcing effects of dopamine uptake inhibitors, we investigated the local anesthetic properties of cocaethylene as well as isopropylcocaine, another potential pharmacological tool in studies of cocaine reward and agonist substitution therapy. We compared the efficacy of nerve impulse blockade by lidocaine, cocaine, cocaethylene and isopropylcocaine using rat sciatic nerves and dorsal roots (DRs). Nerves were placed in a modified sucrose gap chamber and repetitively stimulated at high frequency. The amplitude of compound action potentials (CAPs) at the beginning and end of each stimulus train was measured before and after exposure to each compound. All compounds produced concentration-dependent and use-dependent decrements in CAP amplitude, but cocaethylene and isopropylcocaine at medium to high concentration (0.375–1.875 mM) showed a more prolonged block after washout relative to cocaine or lidocaine. Patch clamp studies on dorsal root ganglion (DRG) neurons indicated a use-dependent blockade of sodium channels. These studies provide a more complete understanding of the pharmaocology of potential agonist treatment candidates, and suggest a mechanism whereby cocaethylene produces a decreased euphoria in humans compared to cocaine.

Introduction

Cocaine was the first local anesthetic agent used for surgery. For more than a century, it has been widely viewed as an important tool in anesthesia because of its dual function as a reliable nerve blocking agent and as a potent vasoconstrictor [21]. Cocaethylene and isopropylcocaine are two derivatives of cocaine, differing from their parent compound by only one or two methylene groups, respectively (Fig. 1). While the actions of cocaethylene at monoamine uptake sites have been reported previously, the efficacy of cocaethylene and isopropylcocaine as nerve blocking agents has never been reported.

Cocaethylene became a subject of clinical interest after being identified as a metabolic by-product of concurrent cocaine and ethanol use [10], [13]. Subsequently, cocaethylene has been shown to exert central nervous system effects that have important implications for substance abuse research. In animal studies, cocaethylene has been shown to inhibit neuronal carrier-mediated dopamine uptake [2], [6], [10], [11], [13], a mechanism widely believed to be the source of cocaine reward [19]. While cocaine is roughly equipotent at dopamine, norepinephrine and serotonin uptake sites in the brain, cocaethylene exhibits an approximately seven-fold selectivity for inhibition of dopamine uptake compared to serotonin, and a three-fold selectivity for inhibition of dopamine uptake over norepinephrine in vitro [6]. Human studies have demonstrated that cocaethylene generates less euphoria and cardiovascular sequelae than cocaine [9], [16], [17]. There is continued interest in cocaethylene both as a pharmacological tool for examining the neurochemical basis of cocaine reward and as a potential model compound for agonist-based approaches to cocaine dependence [3]. It was recently reported that local anesthetic properties may influence the intensity of reward induced by dopamine uptake inhibitors [24]. Thus, it is important to characterize the local anesthetic effects of cocaethylene and isopropylcocaine in order to: (1) determine if differences in them may contribute to differences in euphoric effects from cocaine; (2) add a crucial dimension to our understanding of the complex pharmacology of potential agonist treatments.