Water diffusion, T(2), and compartmentation in frog sciatic nerve.

A potential relationship between structural compartments in neural tissue and NMR parameters may increase the specificity of MRI in diagnosing diseases. Nevertheless, our understanding of MR of nerves and white matter is limited, particularly the influence of various water compartments on the MR signal is not known. In this study, components of the (1)H transverse relaxation decay curve in frog peripheral nerve were correlated with the diffusion characteristics of the water in the nerve. Three T(2) values were identified with nerve. Water mobility was found to be unrestricted on the timescale of 100 msec in the component of the signal with the intermediate T(2) time, suggesting some contribution from the interstitial space to this T(2) component. Restricted diffusion was observed in the component with the longest T(2) time, supporting the assignment of at least part of the spins contributing to this component to an intracellular compartment. The observed nonexponential behavior of the diffusion attenuation curves was investigated and shown to be potentially caused by the wide range of axon sizes in the nerve. Magn Reson Med 42:911-918, 1999.

Electrophysiological evidence for tetrodotoxin-resistant sodium channels in slowly conducting dural sensory fibers.

A tetrodotoxin (TTX)-resistant sodium channel was recently identified that is expressed only in small diameter neurons of peripheral sensory ganglia. The peripheral axons of sensory neurons appear to lack this channel, but its presence has not been investigated in peripheral nerve endings, the site of sensory transduction in vivo. We investigated the effect of TTX on mechanoresponsiveness in nerve endings of sensory neurons that innervate the intracranial dura. Because the degree of TTX resistance of axonal branches could potentially be affected by factors other than channel subtype, the neurons were also tested for sensitivity to lidocaine, which blocks both TTX-sensitive and TTX-resistant sodium channels. Single-unit activity was recorded from dural afferent neurons in the trigeminal ganglion of urethan-anesthetized rats. Response thresholds to mechanical stimulation of the dura were determined with von Frey monofilaments while exposing the dura to progressively increasing concentrations of TTX or lidocaine. Neurons with slowly conducting axons were relatively resistant to TTX. Application of 1 microM TTX produced complete suppression of mechanoresponsiveness in all (11/11) fast A-delta units [conduction velocity (c.v.) 5-18 m/s] but only 50% (5/10) of slow A-delta units (1.5

Opioid therapy for chronic noncancer back pain. A randomized prospective study.

STUDY DESIGN: A randomized, open, long-term, repeated-dose comparison of an anti-inflammatory drug and two opioid regimens in 36 patients with back pain. OBJECTIVES: To examine the long-term safety and efficacy of chronic opioid therapy in a randomized trial of patients with back pain. METHODS: All participants underwent a 4-week washout period of no opioid medication before being randomly assigned to one of three treatment regimens for 16 weeks: 1) naproxen only, 2) set-dose oxycodone, or 3) titrated-dose oxycodone and sustained-release morphine sulfate. All patients then were assigned to a titrated dose of opioids for 16 weeks and then gradually tapered off their medication for 12 weeks. Finally, all participants were monitored for a 1-month posttreatment washout period. Each patient was called once a week for a report on pain, activity, mood, medication, hours awake, and adverse effects and was monitored carefully for signs of abuse and noncompliance. RESULTS: Weekly reports during the experimental phase showed the titrated-dose group to have less pain (P < 0.001) and less emotional distress (P < 0.001) than the other two groups. Both opioid groups were significantly different from the naproxen-only group. During the titration phase, patients also reported significantly less pain and improved mood. Few differences were found in activity or hours asleep, or between average pretreatment and posttreatment phone-interview and questionnaire variables. No adverse events occurred, and only one participant showed signs of abuse behavior. CONCLUSIONS: The results suggest that opioid therapy has a positive effect on pain and mood but little effect on activity and sleep. Opioid therapy for chronic back pain was used without significant risk of abuse. However, tapered-off opioid treatment is palliative and without long-term benefit.

Susceptibility to lidocaine of impulses in different somatosensory afferent fibers of rat sciatic nerve.

Mechanosensitive A beta-fibers (n = 29) and nociceptive A delta- (n = 6) and C-fibers (n = 10) of the rat sciatic nerve were superfused with lidocaine (LID, 0.1-1.4 mM) in vivo. The [LID] to abolish single electrically stimulated impulses (tonic blockade) in axons was 0.2 to 0.8 mM for A beta-, 0.1 to 0.6 mM for A delta- and 0.1 to 1.4 mM for C-fibers. Within each of the fiber groups there was no dependence of blocking [LID] on conduction velocity; slower fibers were no more susceptible than faster ones. Mean blocking concentrations differed between groups, with C-fibers having an IC50 = 0.80 +/- 0.32 mM (+/- S.E.), significantly higher (P < .05, ANOVA) than A beta-fibers (IC50 = 0.41 +/- 0.15 mM) and A delta-fibers (IC50 = 0.32 +/- 0.18 mM). The [LID] causing 50% impulse failure in A beta-fibers during a 200-Hz, 10-stimulus train (phasic blockade) ranged from 0.2 mM to 0.7 mM; the mean IC50 equaled 0.28 mM (n = 17). Stimulation of nociceptive A delta-fibers (n = 4) and C-fibers (n = 5) at 5 or 10 Hz for 10 pulses produced no phasic block at [LID]s (0.1-0.5 mM) below those required for tonic blockade. Uptake of 14C-lidocaine by the nerve, measured in vivo under conditions identical with those for electrophysiology, showed that: a) little drug was in the segments of nerve beyond the superfusion chamber, b) lidocaine was uniformly distributed in the nerve within the chamber, c) the intraneural lidocaine content was identical with that in nerves equilibrated in vitro. The results show a lack of monotonic dependence of sensitivity to local anesthetic on fiber diameter, but do suggest that mean susceptibility to nerve block by lidocaine differs for fibers grouped by, and perhaps according to, function.

On the origin of headaches.

Headache is one of the most common types of pain, but its causes remain poorly understood. The long-standing idea that some headaches, particularly migraine, might be caused by cerebral or cranial vasodilation has failed to find support in recent studies. Alternative hypotheses have focused on other processes that might be capable of activating or sensitizing sensory nerve fibres that innervate the blood vessels of the intracranial meninges.

Sensitization of meningeal sensory neurons and the origin of headaches.

The headaches that accompany certain intracranial pathologies (such as meningitis, subarachnoid haemorrhage and tumour) have been considered to result from mechanical or chemical stimulation of pain-sensitive structures of the intracranial meninges. Although the recurrent headache of migraine is of unknown origin and is not accompanied by an identifiable pathology, it shares with intracranial headaches features that suggest an exaggerated intracranial mechanosensitivity (worsening of the pain by coughing, breath-holding or sudden head movement). One possible basis for such symptoms would be a sensitization of meningeal afferents to mechanical stimuli. Previous studies of neuronal responses to meningeal stimulation have focused primarily on cells in the central portion of the trigeminal pathway, and have not investigated the possible occurrence of sensitization. We have recorded the activity of primary afferent neurons in the rat trigeminal ganglion that innervate the dural venous sinuses. Chemical stimulation of their dural receptive fields with inflammatory mediators both directly excited the neurons and enhanced their mechanical sensitivity, such that they were strongly activated by mechanical stimuli that initially had evoked little or no response. These properties of meningeal afferents (chemosensitivity and sensitization) may contribute to the intracranial mechanical hypersensitivity that is characteristic of some types of clinically occurring headaches, and may also contribute to the throbbing pain of migraine.

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.

Potentiation by capsaicin of lidocaine's phasic impulse block in isolated rat sciatic nerve.

Compound action potentials (CAPs) of A- and C-fibres were recorded from isolated sciatic nerves of the rat to determine whether lidocaine-induced phasic impulse block was affected by low doses of capsaicin. Preceding impulse activity produced phasic reductions of the amplitudes of both A- (5.7 +/- 1.3%) and C-CAPs (20.7 +/- 7.0%) in drug-free solution. Capsaicin alone (50 microM) did not change the activity-induced reductions of the heights of both CAPs (A-CAP: 6.2 +/- 1.7%, C-CAP: 22.3 +/- 8.0%). Lidocaine (100 microM) caused differential phasic blocks between the A-CAP (20.1 +/- 3.7%; n = 7) and the C-CAP (33.8 +/- 4.9% n = 7). Lidocaine's phasic impulse block was potentiated after 30 min of subsequent capsaicin administration (A-CAP: 40.6 +/- 4.7%, n = 7; C-CAP: 48.8 +/- 5.5% n = 9). Capsaicin's phasic potentiating effects were reversed after 30 min of washing. These results suggest that capsaicin may be a useful agent for the reversible potentiation of phasic impulse blockade by lidocaine.

Potentiation by capsaicin of lidocaine's tonic impulse block in isolated rat sciatic nerve.

Compound action potentials (CAPs) of A- and C-fibers were recorded from isolated sciatic nerves of the rat to determine whether tonic block of impulse conduction induced by lidocaine was affected by low doses of capsaicin. Capsaicin alone (50 microM) did not change the CAPs of either A- or C-fibers. Although the lower concentrations of capsaicin (5-30 microM) caused no change of the tonic blocking action of lidocaine, 30 min of 50 microM capsaicin administration did induce a significant potentiation of tonic block. Capsaicin's potentiating effects were partially reversed after 30 min of wash. These results suggest that capsaicin may be a useful agent for the potentiation of impulse blockade by lidocaine.

Activity-dependent variations in conduction velocity of C fibers of rat sciatic nerve.

Changes in the conduction velocity and subsequent conduction block were characterized following impulse activity in single C fibers of rat sciatic nerves. C fibers which had the same resting conduction velocities often exhibited quite different profiles of the activity-dependent latency change and/or conduction block following impulses. The results imply underlying variation among C fibers in the activity-dependent excitability changes, especially in the build-up and recovery of the hypoexcitable phases.

Modality-dependent modulation of conduction by impulse activity in functionally characterized single cutaneous afferents in the rat.

Cutaneous afferents exhibit changes in excitability after impulse activity that are correlated with functional modality but are independent of axonal diameter, as studied in 39 cold fibers and 51 nociceptors of the rat. Latency of conducted impulses was used to indicate changes in axonal excitability caused by electrical stimulation. Stimuli were applied both at fixed frequencies and at the time intervals of impulses previously recorded during response to natural stimulation. Latency increased following both these forms of electrical stimulation, as well as after natural stimulation of the receptive fields. The latency increase was correlated with the number of impulses and the frequency of the preceding discharge in all of 4 nociceptors and 13 cold fibers studied for this feature. Increase of latency by electrical or natural stimulation led to reduced responsiveness to natural stimulation. The magnitude and time course of latency changes were correlated with fiber modality. In 32 nociceptors the latency increased continuously with time during a stimulus train, whereas in 21 cold fibers there was only an initial increase in latency over the first few seconds, after which the latency remained at a plateau even as the firing response continued. Paralleling this slowing, impulse failure occurred more frequently during repetitive stimulation in both A delta and C nociceptors than in velocity-matched cold fibers of either class. Based on the magnitude of latency increases during stimulus trains at different frequencies, two distinct patterns were discerned in A nociceptors: "Type II" fibers slowed significantly more than "Type I" or cold fibers. The results support the hypotheses (1) that the pattern of latency changes during activity are signatures for the modality in a given fiber; and (2) that endogenous, activity-dependent processes of the axon contribute to adaptation and encoding in cutaneous sensory afferents.

On the mechanisms of potentiation of local anesthetics by bicarbonate buffer: drug structure-activity studies on isolated peripheral nerve.

Impulse inhibition by local anesthetics (LAs) is potentiated by extracellular solutions containing HCO3-. CO2 (BC), relative to the inhibition in BC-free solutions at the same pH. We studied the mechanistic basis of this potentiation by assaying compound action potential amplitudes in desheathed frog sciatic nerves with the sucrose-gap method. We compared the potencies of 12 different impulse-blocking agents in Ringer's buffered with BC (BC-R) and in Ringer's containing only atmospheric CO2 and buffered by a zwitterionic compound (3-(N-morpholino)propanesulfonic acid-Ringer's). The relative inhibition produced by an agent in BC divided by the inhibition produced in 3-(N-morpholino)propanesulfonic acid, was defined as the potentiation factor (PF). The organic guanidinium blockers of sodium channels, tetrodotoxin and saxitoxin, which act at a different site from that for LAs, were, by our definition, nominally potentiated (PF = 1.33 +/- 0.04, mean +/- SEM, n = 4, and 1.24 +/- 0.07, n = 10, respectively), implying that BC induces a decrease in the safety margin for impulse conduction, a decrease that cannot itself alone account for the much larger potentiation (PF = 5-8) by BC observed with certain LAs. Only nominal potentiations occurred with charged LAs (PF = 1.15), showing that little direct potentiation of the cationic LA species per se occurs. Inhibition by the permanently neutral LA benzocaine had a significantly larger than nominal potentiation (PF = 1.8) showing that BC can potentiate neutral LAs. Among the tertiary amine LAs, potentiation of ester-linked drugs (procaine, RAG505; PF = 3.9, 5.4, respectively), exceeded that of their amide-linked homologues (procainamide, lidocaine; PF = 1.3, 2.8, respectively) which have higher pKa values. This result is consistent with an ion trapping mechanism whereby CO2 acidifies the axoplasm and thereby increases the concentration of protonated LA inside the nerve fibers. However, slight differences in the molecular structure of 3 degrees-amine LAs with similar pKa values resulted in significantly different potentiations (e.g., procaine, PF = 3.9; 2-chloroprocaine, PF = 8.7), suggesting that the HCO3- or CO2 molecules interact specifically with the LA molecule or with LA binding sites in the nerve membrane. Spectrophotometric measurements of the free [Ca2+] in Ringer's showed it to be similar (+/- 0.03 mM) for both buffers, obviating changes in extracellular Ca2+ as a mechanism of BC potentiation. The resting potential of the nerve was slightly more negative (approximately -4 mV) in BC-R, so membrane depolarization cannot explain the potentiation.(ABSTRACT TRUNCATED AT 400 WORDS)

Subblocking concentrations of local anesthetics: effects on impulse generation and conduction in single myelinated sciatic nerve axons in frog.

Phenomena seen in axons exposed to subblocking doses serve as the basis for interpreting clinical and behavioral observations during onset and recovery of peripheral nerve block. To delineate the changes in excitability and in impulse conduction caused by subblocking concentrations of local anesthetics (LAs) in myelinated peripheral nerve fibers, LAs were applied to excised frog sciatic nerves while impulse conduction was monitored in single axons. For concentrations ranging from 0.01 to 1.2 times the LA concentration needed to block impulse conduction, three measures of susceptibility to LA were made to quantify the action of the drugs on "resting" fibers (firing rates < or = 0.5 Hz): the increase in the threshold for electrical activation of impulses, the increase in conduction latency reflecting the slowing of impulse conduction in the region exposed to LA, and the "critical blocking concentration" of LA just sufficient to prevent impulse conduction in the recorded fiber. Wide interfiber variation in these variables was observed (e.g., for lidocaine, latency increases at block ranged from 66% to 257% of control, blocking concentrations ranged from 0.29 to 1.40 mM), which was not correlated with fiber diameter (as indicated by resting conduction velocity). Mathematical modeling of impulse conduction in fibers exposed to LA demonstrated that the interfiber variation in susceptibility to LA block could result from interfiber differences in the density of sodium and potassium channels. The effects of LA were also studied in active fibers (firing rates > 0.5 Hz). Local anesthetics reversibly inhibited two normally occurring afteroscillations in membrane threshold related to afterpotentials following an impulse. These were "superexcitability," a transient lowering of threshold lasting as long as 1 s, and "depression," a phase of raised threshold peaking within 2-4 s after an impulse and recovering slowly over several minutes. Impulse activity also transiently increased the apparent potency of LAs. Such "use-dependent" increases in threshold and decreases in conduction velocity showed kinetics that were agent specific, lasting 1 s after a burst of impulses for lidocaine and lasting > 10 s for bupivacaine. At low concentrations, within the range of nontoxic plasma concentrations after systemic administration, the predominant actions of LAs on conducting fibers were transient decreases in excitability and conduction velocity in combination with a reduction of intrinsic oscillatory aftereffects of impulse discharge. These effects may degrade decoding of information in discharge patterns without actually blocking conduction of infrequent impulses, suggesting how functional blockade of coordinated movement and perception may occur even without complete blockade of impulse conduction.

The NerveSeeker: a system for automated nerve localization.

BACKGROUND AND OBJECTIVES: The NerveSeeker is a new instrument for locating peripheral nerves. Like existing nerve stimulators, it is based on injecting current through the needle used for drug injection. However, the NerveSeeker was designed to automatically adjust the amplitude of the stimulating current pulses. It does this by feedback control to hold the level of response constant at a small but reliably detectable fraction of a maximal neural response. We report experimental tests of the NerveSeeker using an excised frog nerve in a transparent chamber, where we could observe the needle approach. METHODS: A control voltage proportional to the stimulus magnitude was used to indicate the proximity of the needle tip to the nerve. The proximity was validated by direct measurement of the distance from the tip of the needle to the nerve. Parameters governing the performance of the NerveSeeker in tracking needle movement were analyzed. RESULTS: The following combined strategy was found effective: As the needle approached the nerve, the stimulus was reduced in proportion to the amplitude of the recorded response; as the needle moved away, the stimulus magnitude was incremented by a constant amount (enough to increase the neural response by approximately 1% of its maximum amplitude) after each stimulus that failed to elicit a neural response exceeding the criterion value. Stimulation throughout simulated penetrations was at a frequency of 10 Hz or higher to give more immediate guidance during insertion. Optimal settings for each control parameter were determined, reflecting both engineering and physiologic tradeoffs. With these settings, the device proved successful in localizing nerves, closely tracking needle movements at velocities as high as 2 mm/second. CONCLUSION: These experimental results suggest that clinical tests of the NerveSeeker would be appropriate.

Effects of PVN lesions on the responsiveness of female rats to estradiol.

Previous research has shown that the paraventricular nucleus of the hypothalamus (PVN) is an important site of action for the effects of estradiol on feeding behavior. The recent finding that estrogenic stimulation of the PVN lowers food intake without inducing lordosis suggests that the effects of estradiol on feeding and sexual behaviors are organized separately within the brain. Whether the effects of estradiol on food intake can be attenuated by PVN lesions is therefore a question of practical and theoretical interest. In this experiment we examined the behavioral responsiveness of females with PVN lesions to peripheral treatment with estradiol. 32 adult, female rats received either bilateral or sham lesions of the PVN. All subjects were ovariectomized 2 weeks after the lesion. 2 Weeks following ovariectomy, half of the animals were injected with 2 micrograms of estradiol benzoate (EB) for 3 days, and half were injected with the oil vehicle. 10 days later, the treatment conditions for each subject (oil or EB) were reversed. Histological analysis indicated that 9 females had bilateral lesions of the PVN and 4 had bilateral lesions of the dorsomedial nucleus of the hypothalamus (DMN); 11 animals received sham lesions. Compared with oil treatment, EB injections significantly lowered water intake and body weight gain in all groups. However, food intake was suppressed in the DMN and sham but not in PVN-lesioned females. In addition, statistical analyses indicated that EB treatment induced similar levels of female sexual behavior in all groups. Thus, PVN lesions did not interfere with the ability of estradiol to stimulate lordosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Excitability changes in C fibers of rat sciatic nerve following impulse activity.

Three phases in the oscillatory changes of both threshold and conduction velocity were identified following impulse activity in single C fibers of rat sciatic nerves. These after-oscillations, occurring after the refractory period, varied with the number and timing of preceding 'conditioning' impulses. The excitability changes differed both qualitatively and quantitatively among fibers, thus implying underlying variation among C fibers in the density and distribution of voltage-gated channels and ion pumps.

Changes in axonal impulse conduction correlate with sensory modality in primary afferent fibers in the rat.

Conduction velocity was measured in vivo in single cutaneous afferent fibers of rat sciatic nerve that were characterized by natural stimulation. During sustained electrical stimulation, impulses slowed less and propagated more reliably in cold fibers (both A delta and C) than in nociceptive fibers of similar conduction velocity. Velocity in cold fibers tended to stabilize after an initial decrease rather than decrease throughout the stimulation as for nociceptive fibers. The slowing correlated with axon modality and hence with natural firing pattern, raising the possibility that impulse activity can determine conduction properties of axons.