Johann G. Thalhammer

Effects of Halothane on Spinal Neuronal Responses to Graded Noxious Heat Stimulation in the Cat

This study was undertaken to examine the dose–response effects of clinical concentrations of halothane on activity of widedynamic-range (WDR) neurons in the dorsal horn of the spinal cord of the decerebrate, spinal cord-transected cat. All cells (n = 40) responded maximally to high-intensity (greater than 45 C) noxious heat stimulation. Following administration of halothane, 0.5, 1.0, and 1.5 per cent, the mean spontaneous discharge frequency was significantly decreased (P < 0.01) by 44, 74, and 87 per cent, respectively. The mean evoked discharge frequencies were also significantly decreased at all temperatures (46, 48.5, 51 C) by all concentrations of halothane. The slope of the regression line relating heat intensity and evoked neuronal discharge frequency was significantly decreased (P < 0.01) with both 1.0 and 1.5 per cent halothane by 46 and 75 per cent, respectively. Since the spinal cord was transected, these results indicate that these effects were the result of a direct action at the level of the spinal cord. The neuronal activity that was suppressed was evoked by stimuli that were exclusively noxious. This substantiates the ability of halothane to modify the transmission of noxious information at the spinal cord level, and thus explains a mechanism by which halothane may induce analgesia.

Quaternary Ammonium Derivative of Lidocaine as a Long-acting Local Anesthetic

Background Use of long‐acting local anesthetics that elicit complete neural blockade for more than 3 h often is desirable in pain management. Unfortunately, clinically available local anesthetics are in general not suitable for prolonged analgesia. This report describes the organic synthesis and functional testing of a lidocaine derivative that appears to fulfill the criteria of long‐acting local anesthetics.

N-Butyl Tetracaine as a Neurolytic Agent for Ultralong Sciatic Nerve Block

Background Neurolytic agents such as phenol (5% to 10%) and absolute alcohol have long been used clinically to destroy the pathogenic nerve regions that manifest pain. Both phenol and alcohol are highly destructive to nerve fibers. However, these agents exert only weak local anesthetic effects and therefore are difficult to administer to alert patients without pain. This report describes a tetracaine derivative that displays both local anesthetic and neurolytic properties. Studies with such a compound may lead to the design of neurolytic agents that are more effective and more easily administered than phenol and alcohol. Methods A tetracaine derivative, N-butyl tetracaine quaternary ammonium bromide, was synthesized, and its ability to elicit sciatic nerve block of sensory and motor functions in vivo was tested in rats. A single dose of 0.1 ml N-butyl tetracaine at 37 mM was injected into the sciatic notch. Transverse sections of treated sciatic nerves were subsequently examined to determine the neurolytic effect of this drug. Finally, the local anesthetic properties of N-butyl tetracaine were studied in vitro; both tonic inhibition and use-dependent inhibition of Sodium sup + currents in neuronal GH3 cells were characterized under whole-cell voltage-clamp conditions. Results N-butyl tetracaine at 37 mM (equivalent to 1.11% tetracaine-hydrochloric acid concentration) elicited prolonged sciatic nerve block of the withdrawal response to noxious pinch in rats for more than 2 weeks. The withdrawal response was fully restored after 9 weeks. Parallel to sensory block, motor functions of the hind legs were similarly blocked by this drug. Morphologic examinations 3 and 5 weeks after a single injection of drug revealed degeneration of many sciatic nerve fibers, consistent with the results of functional tests. Finally, N-butyl tetracaine was found to be a potent Sodium sup + channel blocker in vitro. It produced strong tonic and use-dependent inhibition of Sodium sup + currents with a potency comparable to that of tetracaine. Conclusions A single injection of N-butyl tetracaine produces ultralong sciatic nerve block in rats. This compound possesses both local anesthetic and neurolytic properties and may prove useful as a neurolytic agent in pain management.

Mechanoreceptive afferents exhibit functionally-specific activity dependent changes in conduction velocity.

Impulse activity in axons generates aftereffects on membrane excitability that can alter the conduction velocity of subsequently conducted impulses. We used a computerized stimulus pattern (a 1 Hz stimulus period followed by a period of repeated short bursts at 200 Hz) to assess in vivo activity-dependent changes in conduction latency of functionally identified rat cutaneous afferents conducting in the A beta range. Several different parameters of activity dependence were measured: burst supernormality, the average increase in conduction latency following conditioning with a single preceding impulse during high frequency burst stimulation; burst subnormality, the average latency increase during each burst; depression, a long-term increase in latency caused by the high frequency stimulation. The data show that different mechanosensitive A beta afferents with overlapping resting conduction velocities exhibit activity-dependent changes in conduction latency that are characteristic of their particular functions.

Structure-activity relation of N-alkyl tetracaine derivatives as neurolytic agents for sciatic nerve lesions

Background N‐butyl tetracaine has local anesthetic and neurolytic properties. An injection of this drug at the rat sciatic notch produces rapid onset and nerve impairment lasting > 1 week. This study aimed to elucidate the structure‐activity relation of various tetracaine derivatives to design better neurolytic agents. Methods N‐alkyl tetracaine salts (n = 2–6) were synthesized, and their ability to elicit sciatic nerve impairment of sensory and motor functions in vivo was tested in rats. A single dose (0.1 ml at 37 mM) was administered close to the sciatic nerve at the sciatic notch. Regeneration was assessed morphologically in transverse sections of treated nerves. Finally, the drug potency in blocking Na sup + currents was studied under voltage‐clamp conditions. Results N‐ethyl and N‐propyl tetracaine derivatives were non‐neurolytic and elicited complete sciatic nerve block lasting 3–7 h. In contrast, N‐butyl, N‐pentyl, and N‐hexyl tetracaine derivatives were strong neurolytic agents and elicited functional impairment of sciatic nerve for > 1 week. All derivatives were strong Na sup + channel blockers, more potent than tetracaine if applied intracellularly. External drug application showed marked differences in their wash‐in rate: tetracaine > N‐hexyl > N‐butyl > N‐ethyl tetracaine. All derivatives were trapped within the cytoplasm and showed little washout within 7 min. Conclusions When n‐alkylation is 4–6, n‐alkyl tetracaine appeared as a strong neurolytic agent. Neurolytic derivatives retained their local anesthetic activity and elicited rapid onset of nerve block after injection. Such derivatives are potential local anesthetic‐neurolytic dual agents for chemical lesions of the sciatic nerve.

Behavioral evidence of thermal hyperalgesia in non-obese diabetic mice with and without insulin-dependent diabetes

The non-obese diabetic (NOD) mouse, a model of Type 1 diabetes in humans, has proven useful for the study of genetic, immunologic and epidemiologic aspects of inherited diabetes. Behavioral evidence of hyperalgesia may also be present in the NOD mouse but has not been described. This study examined NOD mice with (NOD+) and without (NOD-) insulin-dependent diabetes, and control strain (ILI) mice for evidence of hyperalgesia to a noxious thermal stimulus. Interestingly, both NOD+ and NOD- mice showed reduced mean hindpaw withdrawal latencies when compared with non-diabetic ILI mice. NOD+ and NOD- mice were also abnormal in their general appearance, activity level, posture, gait and muscle bulk when compared with ILI mice. These findings raise the possibility that hyperalgesia in insulin-dependent NOD mice, or insulin-dependent humans with Type 1 diabetes, may be independent of diabetes and due to a primary disturbance within sensory pathways.

Neurophysiologic Actions and Neurological Consequences of Veratridine on the Rat Sciatic Nerve

Background: The quest for a drug that would provide analgesia with minimal motor deficiency, through the selective inhibition of impulses in small‐diameter fibers, was brightened by a previous report of veratridines C‐fiber‐selective actions on the isolated rabbit vagus nerve. The goal of the present research was to demonstrate the same actions on rat sciatic nerve in vitro and to observe the functionally differential blockade in the rat in vivo. Methods: Sciatic nerves were removed from rats, mounted in a recording chamber, wherein a 1‐cm length of the ensheathed nerve was superfused with the plant alkaloid veratridine (2 micro Meter) in bicarbonate‐buffered Lileys solution, and the compound action potential (CAP) was stimulated supramaximally to give A‐ and C‐fiber elevations. Onset, steady‐state, and recovery from veratridine effects were assayed for a range of stimulus frequencies. Open‐field behavior and quantitative neurological assessments of proprioception, motor function, and nociception were tested in 15 trained rats after injection near the sciatic nerve of 0.1 ml veratridine at 0.5, 0.7, and 1.0 mM each plus epinephrine (1:200,000). Results: Veratridine inhibited the C‐fiber component of the CAP in a frequency‐dependent manner. At 0.1 Hz the CAP was 65% of the control amplitude, 50% at 0.5 Hz, and 40% at 5 Hz. A‐fiber elevations were unattenuated at stimulus frequencies as high as 50 Hz. Steady‐state inhibition was reached 5 min after drug administration, and recovery from the effects was 30% complete by 15 min of drug washout. Proprioception, measured as a “hopping” or “placing” reaction, was inhibited dose dependently by maximum degree and for durations of, respectively, 0.5 mM, 61%, 180 min; 0.7 mM, 100%, 360 min; and 1 mM, 100%, 420 min. Extensor postural thrust, as a measure of motor function, was inhibited by and for 0.5 mM, 77%, 240 min; 0.7 mM, 99%, 390 min; and 1 mM, 100%, 420 min. Analgesia, as a prolonged withdrawal latency to a noxious thermal stimulus, had the following profile: 0.5 mM, 10%, 30 min; 0.7 mM, 52%, 150 min; and 1 mM, 66%, 150 min. Conclusions: Despite the fact that veratridine gave a C‐fiber preferential blockade in the isolated sciatic nerve, heightened analgesia over motor block was not achieved in vivo. Indeed, just the opposite occurred. If preferential C‐fiber blockade also occurs in vivo, then its traditionally expected correlation with analgesia must be re‐examined.