dizocilpine-maleate and chloroprocaine

A model of local anesthetic tachyphylaxis was developed in our group previously using repeated sciatic nerve blocks in rats. In this model, thermal hyperalgesia accelerated tachyphylaxis, and the noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, MK-801, prevented both hyperalgesia and tachyphylaxis. Nitric oxide is thought to be a second messenger for NMDA pathways in the spinal cord, and appears to be involved in spinal mechanisms of hyperalgesia. We hypothesized that nitric oxide synthase inhibitors would also inhibit the development of tachyphylaxis. Repeated rat sciatic nerve blocks were placed by percutaneous injection of 2-chloroprocaine. Block duration was tested by measuring hot-plate latency at 56 degrees C. Two hours before the first nerve block, rats received intraperitoneal injections with saline or one of six concentrations of NG-nitro-L-arginine methyl ester (L-NAME) in a randomized, blinded pattern. Control rats developed tachyphylaxis as seen previously: the duration of the third block was 30% that of the first. L-NAME inhibited the development of tachyphylaxis in a dose-dependent manner; tachyphylaxis was inhibited by 50% using L-NAME at 0.2mg/kg and completely abolished by 50 mg/kg. Nitric oxide pathways may be involved in the development of tachyphylaxis to local anesthetic nerve block.

Topics: Anesthetics, Local; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Hot Temperature; Hyperalgesia; Male; Nerve Block; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Procaine; Random Allocation; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, N-Methyl-D-Aspartate; Sciatic Nerve; Second Messenger Systems; Spinal Cord; Tachyphylaxis

Tachyphylaxis to local anesthetics has been shown to be promoted by longer interanalgesic intervals between injections. We hypothesized that thermal hyperalgesia also would accelerate the development of tachyphylaxis. The n-methyl-D-aspartate antagonist ((+)-5 methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine, or dizocilpine) (MK-801) has been shown to prevent thermal hyperalgesia. We therefore also hypothesized that MK-801 would prevent tachyphylaxis.. Catheters were surgically implanted in rats along the sciatic nerve. After recovery and conditioning to the testing paradigm, they received repeated injections of lidocaine or 2-chloroprocaine followed by motor block testing with or without hot-plate testing at 48, 52, or 56 degrees C. In other experiments, MK-801 or saline was administered by intraperitoneal injection before sciatic nerve local anesthetic injection and sensory and motor testing.. Rats receiving repeated lidocaine or 2-chloroprocaine injections, when repeatedly subjected to hot-plate testing at 56 degrees C, developed thermal hyperalgesia and tachyphylaxis to motor and sensory blockade. Rats receiving either no hot-plate exposure or hot-plate exposure at 48 degrees C developed no tachyphylaxis or hyperalgesia. Rats tested at 52 degrees C developed milder hyperalgesia and developed tachyphylaxis more slowly than did rats tested at 56 degrees C. Control experiments excluded artifacts due to circadian rhythm, injection volume, and learning. Rats pretreated with MK-801 showed no tachyphylaxis over a series of three injections.. Thermal hyperalgesia accelerates the development of tachyphylaxis to rat sciatic nerve blockade, and MK-801 prevents tachyphylaxis in this model. n-Methyl-D-aspartate receptor antagonists may have future clinical utility in increasing the duration of effectiveness of prolonged local anesthetic administration.

Topics: Animals; Circadian Rhythm; Dizocilpine Maleate; Hot Temperature; Hyperalgesia; Male; Nerve Block; Procaine; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Tachyphylaxis