Lisa C. Russell

The effect of intravenous lidocaine, tocainide, and mexiletine on spontaneously active fibers originating in rat sciatic neuromas

&NA; The effects of intravenously administered subanesthetic concentrations of lidocaine, tocainide, and mexiletine on spontaneously active fibers (SAFs) originating in 7‐day‐old rat sciatic neuromas were studied. Control injections of normal saline caused no decrease in SAF or discharge rate. Lidocaine and tocainide given in incremental doses of 5, 10, 15, 20 and up to 25 mg/kg caused nearly all observed SAFs to stop firing. Mexiletine given in doses of 3, 5, 7, 10 and up to 15 mg/kg showed similar results at lower doses. All agents decreased the sensitivity of SAF to mechanical stimulation. No conduction blockade occurred at these doses of intravenously administered local anesthetics. The demonstrated reduction in firing rate of SAF may explain the pain relief observed in clinical trials of these orally available agents.

Pain responses to perineuromal injection of normal saline, gallamine, and lidocaine in humans.

&NA; Rat neuromas have shown an increase of spontaneously active fibers to systemically administered potassium channel blocking agents such as tetraethylammonium chloride (TEA) and gallamine. Neuroma formation and spontaneous activity have been associated with autotomy in rats and pain in humans. To evaluate the chemosensitivity of human neurons to potassium channel blocking agents, 9 subjects with neuroma pain underwent perineuromal injection in a single‐blinded fashion of normal saline, gallamine, and lidocaine. Sodium chloride had no effect on control pain levels, while gallamine significantly increased and lidocaine significantly decreased pain from control levels. Three of 4 patients with accompanying phantom limb pain noted an increase in pain after the injection of gallamine. The data suggest that peripheral input plays a modulating but not solitary role in both neuroma and phantom limb pain. Agents which increase potassium channel permeability or decrease sodium influx would be predicted to decreased perceived pain.

Spontaneous activity of primary afferent neurons in diabetic BB/Wistar rats: A possible mechanism of chronic diabetic neuropathic pain

The mechanism of painful diabetic neuropathy remains unknown. Spontaneous activity in nociceptive primary afferents has been implicated in the genesis of chronic pain due to peripheral nerve injury, and diabetic axonopathy shares some histologic features with traumatic neuropathy. We hypothesized that spontaneous hyperactivity of nociceptive neurons might represent the neurophysiologic mechanism of diabetic neuropathic pain. To test this, we examined the spontaneous activity of primary afferent axons from diabetic BB/Wistar and normal Wistar rat saphenous nerves isolated from central and peripheral connections. Microfilament recordings from diabetic nerves showed a significantly higher incidence of spontaneous discharges in comparison to normal nerves. Furthermore, this spontaneous hyperactivity occurred almost exclusively in potentially nociceptive C-fibers. We conclude that in the diabetic BB/Wistar rat, spontaneous impulses are generated in potential nociceptive primary afferent neurons, and that this may represent the mechanism of chronic diabetic neuropathic pain.

Reduction of Extraneural Scarring by ADCON-T/N after Surgical Intervention

The effects of ADCON-T/N (Gliatech, Inc., Cleveland, OH), a carbohydrate polymer gel, on peripheral nerve scarring and regeneration were studied in rodents undergoing three types of surgical intervention. Procedure I involved external neurolysis of the sciatic nerve from surrounding tissues and separation of its tibial and peroneal components. Procedure II involved the addition of an abrasive injury. Procedure III involved transection and suture anastomosis of the tibial component. ADCON-T/N or a control gel was locally applied in a blind fashion. Additional animals received no gel, as a further control. Animals underwent second operations 4 weeks after Procedures I and II and 6 weeks after Procedure III. The surgical sites were evaluated using a numerical grading scheme to assess wound healing, sciatic nerve adherence to surrounding tissues, and separability of its tibial and peroneal components. Animals receiving ADCON-T/N demonstrated reduced nerve adherence to surrounding tissues and enhanced separability of the tibial and peroneal components, compared with animals receiving control gel or no gel. Quantitative histological analysis revealed a statistically significant reduction in the amount of dense scar tissue surrounding nerves treated with ADCON-T/N. No evidence of nerve toxicity caused by ADCON-T/N was noted. Counts of regenerating myelinated axons in animals undergoing nerve transection and suture repair did not statistically differ in treated and untreated animals. In conclusion, ADCON-T/N seems to be both safe and effective in reducing extraneural scar formation after peripheral nerve surgery and local trauma.

Tourniquet-induced limb ischemia: a neurophysiologic animal model.

A rat model of tourniquet-induced ischemia was created to observe the changes in sciatic afferent neuronal activity associated with prolonged tourniquet inflation on the hind leg. The sciatic nerve was divided in the proximal thigh and a two-electrode microfilament recording technique and signal averaging computer were used to survey afferent neuronal activity prior to and after tourniquet inflation. This method was able to determine both firing rate and conduction velocity of spontaneously active or mechanically sensitive nerve fibers. In 14 rats observed prior to tourniquet inflation there was much spontaneous activity. These fibers all had rapid conduction velocities (30 +/- 6.9 m/s) (mean +/- SD) and firing rates (16.3 +/- 1.9 H). All fibers could be stimulated by movement of distal joints or by probing the skin of the leg. After tourniquet inflation, a pressure-induced conduction block occurred stopping all spontaneous and mechanically induced activity. After a short interval, (55 +/- 16 min) a different group of spontaneously active fibers were observed that had both slow conduction (2.04 +/- 0.77 m/s) firing rates (0.54 +/- 0.9 H). These fibers did not respond to mechanical stimulation of the limb distal to the tourniquet, or local anesthetic or cold block of the nerve distal to the tourniquet. Blockade of the sciatic nerve just proximal to the tourniquet and deflation of the tourniquet did abolish activity in these fibers. In ten separate rats in which tourniquets were placed but no surgical incision made, mean arterial blood pressure rose significantly after tourniquet inflation. With tourniquet deflation, blood pressure fell significantly from levels observed during tourniquet inflation.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of intrathecal and subepineural capsaicin on thermal sensitivity and autotomy in rats

&NA; In 79 Sprague‐Dawley rats, we determined the effect of either intrathecal or subepineural capsaicin injection on: (1) latency of withdrawal of the hind foot to a nociceptive thermal stimulus (50 ± 1°C hot plate) and (2) the onset and severity of putative behavioral evidence of chronic pain in the rat (autotomy) which commonly appears following sciatic nerve section. Capsaicin (50 &mgr;g) was suspended in 5 &mgr;l of vehicle (10% Tween‐80 in 0.9% saline) then injected either intrathecally at the level of the L4–5 vertebral interspace or subepineurally in the sciatic nerve at the level of the midfemur. Subepineural capsaicin consistently and efficiently produced thermal analgesia in the rat, while intrathecal capsaicin had no significant analgesic effect. In chronically denervated rats, both subepineural and intrathecal capsaicin decreased the latency to onset of first autotomy, and intrathecal capsaicin increased the severity of this behavior significantly. These data are consistent with the hypothesis that autotomy is the rats response to abnormal sensations perceived in the denervated hind limb. Deafferentation of dorsal horn neurons appears to be of paramount importance in the production of autotomy while the relevance of peripherally originating spontaneous neuroma discharges to autotomy behavior is questioned.

Spontaneous Activity in Afferent and Efferent Fibers after Chronic Axotomy: Response to Potassium Channel Blockade

Distally propagating spontaneous impulses in acutely and chronically cut rat saphenous nerve were examined to determine (1) the origin(s) of the activity, (2) the fiber types involved, and (3) whether the activity was affected by potassium channel blockade. Under deep pentobarbital anesthesia, six male Sprague-Dawley rats underwent L3 cauda equina section, then unilateral saphenous axotomy. The nerve was then dissected into 30-50 microfilaments and surveyed for spontaneous activity using a modification of the microfilament recording method. Afterward, the nerve was cut back, and a potassium channel blocking agent (gallamine) was administered. The axonal activity was once again surveyed in the same fashion. Twenty-eight rats underwent unilateral saphenous axotomy 1-8 weeks prior to similar recordings, and the neuroma was excised just before microfilament dissection. Spontaneous discharges in these preparations originated from three foci: (1) antidromic activity from in-continuity dorsal root ganglia (DRG), (2) orthodromic activity from sympathetic neurons, and (3) antidromic activation of dichotomizing afferent axons in the peripheral nerve. There was significantly more antidromic activity from DRG in rats with prior axotomies than in control animals (t = 2.38; p less than 0.025), and gallamine produced a significant increase in DRG activity in the chronically lesioned nerve (t = 2.43; p less than 0.005), but not in acutely lesioned controls. However, most of the spontaneous activity in these preparations was from sympathetic efferents. This activity was decreased significantly by chronic axotomy (t = 2.635; p less than 0.01), and it was not affected by potassium channel blockade with gallamine. In two microfilaments, spontaneous antidromic action potentials were observed in conjunction with a clear receptive field on blood vessels in the nearby fascia. Both of these presumably dichotomized axons were found in acutely cut nerve, thus were not the result of retrograde sprouting from a neuroma. It was concluded that (1) chronic axotomy of sensory afferents produced ectopic activity in their respective DRG, (2) gallamine administration increased spontaneous activity from DRG in chronically axotomized rats, (3) ongoing sympathetic efferent activity in rat saphenous nerve was decreased by distal axotomy for up to 8 weeks, and (4) rare branched sensory afferents occasionally exhibit spontaneous activity.

Spontaneous activity of primary afferent neurons in diabetic BB/Wistar rats: A possible mechanism of chronic diabetic neuropathic pain : Diabetes, 34 (1985) 1210–1213

The mechanism of painful diabetic neuropathy remains unknown. Spontaneous activity in nociceptive primary afferents has been implicated in the genesis of chronic pain due to peripheral nerve injury, and diabetic axonopathy shares some histologic features with traumatic neuropathy. We hypothesized that spontaneous hyperactivity of nociceptive neurons might represent the neurophysiologic mechanism of diabetic neuropathic pain. To test this, we examined the spontaneous activity of primary afferent axons from diabetic BB/Wistar and normal Wistar rat saphenous nerves isolated from central and peripheral connections. Microfilament recordings from diabetic nerves showed a significantly higher incidence of spontaneous discharges in comparison to normal nerves. Furthermore, this spontaneous hyperactivity occurred almost exclusively in potentially nociceptive C-fibers. We conclude that in the diabetic BB/Wistar rat, spontaneous impulses are generated in potential nociceptive primary afferent neurons, and that this may represent the mechanism of chronic diabetic neuropathic pain.