Biomedical subjects
Publications and source records attributed to S A Raymond.
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.
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.
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.
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.
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.
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.
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.
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.
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)
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)
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.
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.
Explore the source record for details and available documents.
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.
Explore the source record for details and available documents.
1. Firing thresholds and conduction latencies of single myelinated axons in frog sciatic nerves were monitored during impulse activity in vitro. Resting threshold and the activity dependence of threshold were studied as a function of the concentration of two inhalational anaesthetic agents, halothane and enflurane. 2. At concentrations comparable to those obtained during general anaesthesia both agents produced biphasic effects on the resting threshold. A step increase in the partial pressure of anaesthetic was followed first by a transient lowering of threshold, then by a slow rise to a steady-state level above the original baseline. Step decreases in anaesthetic were followed by transient rises before threshold dropped. Transients lasted 20-30 min. During these threshold transients, the average latency of impulse conduction changed monotonically. The prolongation of latency following an increase in anaesthetic was progressive, reaching steady state concurrently with threshold (20 min to greater than 1 h). 3. The anaesthetics reduced the long-lasting increased threshold ('depression') which normally follows repetitive impulse activity in axon membrane. 4. These actions of halothane at concentrations of 0.25-2.7% (0.14-1.54 mM) and enflurane at concentrations of 0.62-3.08% (0.35-1.73 mM) on resting threshold and on the activity-dependent increase in threshold increased monotonically with anaesthetic concentration. 5. The effects on excitability at steady state are consistent with block of voltage-dependent Na+ and K+ channels by these inhalational agents. Reduced depression may occur because the anaesthetics reduce the net ion transfer per impulse, slowing the substrate-driven Na+-K+-ATPase and thereby reducing electrogenic hyper-polarization. 6. The finding that general anaesthetics inhibit depression at clinically relevant concentrations supports the possibility that general anaesthesia is produced by inhibition of processes that modulate excitability of nerve membrane. We suggest that general anaesthetics produce unconsciousness and amnesia because they disrupt activity-dependent processes, which may thus remove temporal 'context' essential for interpreting nerve impulse patterns.
Explore the source record for details and available documents.
The quantitative relation between the concentration of local anesthetic (LA), the length of nerve exposed, and severity of conduction blockade was studied with use of a chamber where exposure length was varied as the concentration of lidocaine was held constant. Recordings of the compound action potential and of single axons established that small variations in the length of nerve exposed to LA strongly modulate conduction block even at exposure lengths in excess of 2 cm. Therefore, exposure length is a significant factor in determining blocking potency, and only at very high concentrations of LA, where voltage-dependent Na conductance is almost completely blocked, is the critical exposure length less than three nodes of Ranvier. The concentration required for 50% block of impulses in single fibers (that is, where 50% of the impulses would fail to propagate through the exposed region of the nerve) diminished as the exposed length of nerve increased, approximately halving as exposure length was changed from 6 mm to 15-25 mm. Conduction latency increased with the exposure length becoming sharply more variable as the critical exposure length for conduction block was approached. The results are consistent with the hypothesis of decremental conduction, where a partial active response in nodes exposed to marginal blocking concentrations extends the decay of the action potential along the axon, and do not support the interpretation that lengths of several centimeters affect blocking concentration because such distances increase the probability that three nodes will be blocked in succession. This study contradicts the broader common assumption that beyond three nodes, the length of nerve exposed is not a factor in nerve block with local anesthetics.