Donald D. Price

Central nervous system mechanisms of analgesia

It has long been recognized that there are central nervous system mechanisms that can strikingly alter the perception of noxious stimuli. Indeed, recent theoretical treatments of pain have often given explicit recognition to this notion although little physiological detail has been available to support it [76,78,83]. The intent of this review is to examine and synthesize the extensive progress that has been made in the last few years describing the anatomical, physiological and neurohumoral substrates of neural systems which modulate pain perception. Particular progress has been made in elucidating a neural system which can be activated by electrical stimulation of certain brain stem structures as well as by the narcotic analgesic drugs. For this reason, considerable emphasis will be placed on explaining its mechanisms. However, we will also review some recent evidence showing that other neural systems as well participate importantly in the modulation of pain.

Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses

&NA; Psychophysical experiments were carried out on 6 human subjects to determine how first and second pain are influenced by peripheral receptor mechanisms and by central nervous system inhibitory and facilitatory mechanisms. For these experiments, brief natural painful stimuli delivered to the hand were a train of 4–8 constant waveform heat pulses generated by a contact thermode (peak temp. = 51.5°C). The magnitude of first and second pain sensations was estimated using cross‐modality matching procedures and reaction times were determined. The latter confirmed the relationship between first and second pain and impulse conduction in A&dgr; and C noxious heat afferents, respectively. The intensity of first pain decreased with each successive heat pulse when the interpulse interval was 80 sec or less. This decrease was most likely the result of heat induced suppression of A&dgr; heat nociceptors since it did not occur if the probe location changed between successive heat pulses. In contrast, second pain increased in intensity with each successive heat pulse if the interval was 3 sec or less. This summation was most likely due to central nervous system summation mechanisms since it also occurred after blockage of first pain by ulnar nerve compression and when the location of the thermode changed between heat pulses. These observations and their interpretations are supported by our recording of responses of single A&dgr; heat nociceptive afferents, C polymodal nociceptive afferents, and “warm” afferents of rhesus monkeys to similar trains of noxious heat pulses. Their responses to these heat pulses show a progressive suppression. Furthermore, previous studies have shown that wide dynamic range dorsal horn neurons show summated responses to repeated volleys in C fibers (Symbol). These spinal cord summation mechanisms could account for the summation of second pain. Symbol. No caption available

Differential effects of spinal cord lesions on narcotic and non-narcotic supression of nociceptive reflexes: Further evidence for the physiologic multiplicity of pain modulation

These studies examined the effects of bilateral lesions of the dorsolateral funiculus (DLF) of the rat spinal cord on the inhibition of a nociceptive reflex produced either by a systemic injection of 4 mg/kg of morphine or by a 20 sec exposure to 1.0 mA of transcutaneous electric shock. Reflex inhibition was quantified and analgesia inferred by use of a modified version of the DAmour-Smith tail-flick test. Lesions which included only the DLF reduced morphine-produced analgesia (MA) by 73% but had no effect on shock-produced analgesia (SA) observed in the same rats. Baseline tail-flick latencies of this group were not affected by the lesions. Control lesions restricted to the dorsal columns attenuated neither MA nor SA. Lesions which included both the dorsal columns and DLF did not affect SA and produced no greater reduction in MA than lesions of the DLF alone. Previous work indicates that both MA and SA result, at least in part, from supraspinal activity. The current data indicate that: (1) supraspinal modulation participating in two different types of analgesic induction involves separate descending spinal pathways and (2) the maximal expression of analgesia produced by administration of narcotics requires the integrity of a supraspinal neural system projecting in the DLF.

Neurophysiological characterization of the anterolateral spinal cord neurons contributing to pain perception in man

Abstract These studies have examined threshold, frequency, and refractory period characteristics of a neural population in the anterolateral quadrant (ALQ) of the spinal cord of man, stimulation of which produces pain. Subjects were 18 conscious humans undergoing percutaneous anterolateral cordotomy for relief of intractable pain. Pain could be produced by ALQ stimulation in all subjects. Pain thresholds ranged from 120 to 1000 &mgr;A (at 50 pulses/sec; 0.2 msec pulses), but the majority of thresholds were below 300 &mgr;A. A linear relationship was found between stimulation frequency and percentage of subjects reporting pain. This relationship ranged from 5 to 25 pulses/sec with 100% reporting pain at 25/sec and 0% at 5/sec. In 2 of 3 subjects, increases in stimulation frequency up to 500/sec did not produce pain when stimulation intensity was below threshold at 50/sec. The neuronal refractory period for pain in these subjects ranged between 1.0 and 2.0 msec, but the majority of relative refractory periods fell between 1.0 and 1.5 msec. The threshold, frequency and refractory period data obtained in this study are similar to those found for wide dynamic range cells in the ventral half of the dorsal horn in the monkey and suggest that activation of these cells is a sufficient condition to produce pain in man.

A psychophysical analysis of experiential factors that selectively influence the affective dimension of pain

&NA; A psychophysical analysis was made of experiential factors that influence the affective but not the sensory‐discriminative dimension of pain. Seven subjects made cross‐modality matching responses to several dimensions of their experience. Before each stimulus, they matched line lengths to their experienced desire to avoid pain (significance) and to their perceived likelihood of avoiding it (expectation). After each stimulus, they matched line lengths to perceived sensation intensity (in some sessions) or to felt magnitudes of positive or negative feeling (in other sessions). Non‐noxious (35, 42°C) and noxious (45–51°C) skin temperature stimuli were randomly interspersed during each experimental session. Changes in expectation were induced by preceding one‐half of the noxious stimuli with a warning signal. The average responses of these subjects indicated that 45–51°C noxious temperatures were felt as less unpleasant when preceded by a warning signal. In contrast, sensation magnitudes evoked by these same skin temperatures were unaffeted by the warning signal. Thus, only the magnitudes of unpleasant responses are lowered by decreasing ones expectation of avoiding pain. Analysis of individual responses revealed two distinct patterns of response changes following presentation of the warning signal. Four subjects retained the same general goal of avoiding pain and reduced their expectation of avoiding it. Their affective responses were less unpleasant during the warning signal. The remaining three subjects primarily altered their goals and not their expectations on signaled trials. Their affective responses were not modified by the signal. Subjects were instructed to arrive at their affective responses in two ways.

Idiopathic trigeminal neuralgia: sensory features and pain mechanisms

&NA; We present a case report of a patient with the typical sensory features of idiopathic trigeminal neuralgia (ITN). The pain was elicited by innocuous stimuli, summated with repeated stimulation, radiated outside the stimulus zone, referred to a distant site, persisted beyond the period of stimulation, and exhibited a variable refractory period. Unusual sensory features included multiple trigger zones that changed over time and involved all 3 trigeminal divisions. Our sensory evaluation indicated that the pain was evoked by repetitive activation of rapidly adapting, A&bgr;, low‐threshold mechanoreceptive afferents. However, activation of such mechanoreceptive afferents alone never produces pain in normal situations and often leads to a suppression of pain responsivity. The findings support the idea that the mechanism of pain in ITN involves pathophysiological mechanisms in the central nervous system. Our hypothesis is that structural and functional changes in the trigeminal system result in an alteration in the receptive field organization of wide‐dynamic‐range (WDR) neurons. There appears to be an alteration in the surround inhibition mechanism of these neurons leading to an expansion of their touch receptive fields. This results in touch stimuli producing activity in WDR neurons that mimics the activity produced under normal conditions by noxious stimuli. Since WDR neurons participate in the encoding of the perceived intensity of noxious stimuli, a series of punctate tactile stimuli are now perceived as localized, pin‐prick or electric shock‐like sensations. Similar pathophysiological mechanisms may explain, in part, the pain of peripheral neuropathies associated with postherpetic neuralgia, diabetes and causalgia.

Neurophysiological characterization of the anterolateral quadrant neurons subserving pain in M. Mulatta

Abstract An electrophysiological analysis has been made of 82 L7 dorsal horn neurons antidromically activated from the contralateral C1 anterolateral quadrant (ALQ) of unanesthetized rhesus monkeys (bilateral carotid ligation). This analysis was made to compare refractory periods and antdromic activation thresholds with these same parameters of ALQ stimulation required to produce pain in conscious humans. Refractory periods of laminae IV‐VI cells that were optimally but not exclusively responsive to noxious skin stimulation ranged from 0.8 to 2.8 msec (Symbol) and were briefer than those of lamina I cells. The latter ranged from 1.1 to 10 msec (Symbol). Electrical thresholds of laminae IV‐VI cells were, in general, much lower than those of laminae I cells. Unlike lamina I cells, refractory periods and electrical thresholds of laminae IV‐VI nociceptive neurons closely parallel those of ALQ‐evoked pain in man. However, both lamina I and laminae IV‐VI neurons usually responded to nociceptive skin temperatures (> 43 °C). This analysis indicates that pain may be signaled by the combined output of dorsal horn laminae I and IV‐VI but that activation of only laminae IV‐VI wide dynamic range neurons is sufficient to produce pain. Symbol. No caption available. Symbol. No caption available.

Spinal cord coding of graded nonnoxious and noxious temperature increases

Abstract Neurons in layers I and IV–VII of L7 and S1 were studied in unanesthetized spinal cats. Each cell was characterized in terms of its responses to electrical stimulation of cutaneous A and C fibers, graded intensities of radiant heat applied to blackened skin, and touch, pressure and pinching. This analysis yielded five classes of units distinguished by the range of mechanical stimuli over which they responded: (I) touch (32 units), (II) touch-pressure (27 units), (III) touch-pressure-pinch (64 units), (IV) pressure-pinch (22 units), and (V) pinch only (9 units). Class I and II cells were concentrated in lamina IV and class III–V cells were distributed in laminae I, IV–VII but mainly in V and VI. In addition to the mechanical classification, some of the class II–V units also responded to radiant heat ( 66 122 ) and were divided into three functional groups. Warming units (10) had threshold skin temperatures between 35 and 42 C and responded maximally below 43 C. Warming-noxious units (14) had threshold responses between 35 and 42 C and maximum responses above 43 C. Noxious heat units (42) had thermal thresholds between 43–50 C and usually had maximum responses at 50 C or higher. Warming units tended to be in class II, warming-noxious units were usually class III units, and noxious heat units were in classes III–V. The responses of warming units indicated that they were adapted for coding the rate of change of skin temperature as well as the skin temperature level within the warming range. Similar to heat-induced pain thresholds and flexion reflexes, noxious heat units responded at the same temperature level (m = 44.5 C) irrespective of the rate of skin temperature change. The response of the population of noxious heat units was linearly related to skin temperature from 43 to 49 C, similar to the psychophysical curve of pain intensity over the same temperature range. Response thresholds of all thermally sensitive units were distributed continuously over a 35–50 C range. Therefore, recruitment of higher threshold units may be an important factor in coding nociceptive information. Representative types of mechanically and thermally sensitive units projected in the ipsilateral dorsolateral columns and their physiological characteristics did not differ from nonprojecting neurons.

The perception of first and second pain as a function of psychological set

The effects of psychological set on perception of first and second pain were determined for 20 subjects. Percutaneous electrical shock intensities (6–8 mA, 3 msec) sufficient to evoke double pain responses were used in all subjects. Psychological sets included PAST (“Place yourself in a previous experience that was free of any significant emotional tone”), PRESENT (“Feel your foot that will be shocked”), and FUTURE (“Think to yourself that you are about to be shocked”). Perception of second pain was never perceived in PAST and FUTURE sets but was always perceived in the PRESENT set. Furthermore, at minimal rates of stimulation ( > 1/3 sec), summation of second pain occurred in the PRESENT set but not in the FUTURE set. All subjects startled in the FUTURE set and did not startle in PAST or PRESENT sets. Each subject reported that the aversiveness of the shock related to painful sensations in PAST and PRESENT sets and to ones own body responses in the FUTURE set.

Trigeminothalamic neurons in nucleus caudalis responsive to tactile, thermal, and nociceptive stimulation of monkeyʼs face

1. A total of 113 trigeminothalamic neurons and over 200 presumed interneurons of nucleus caudalis (0-5 mm below the obex) and subjacent reticular formation were studied in rhesus monkeys anesthetized with chloralose or nitrous oxide. Each cell was characterized in terms of its antidromic responses to stimulation of ventral posterior medial and/or posterior thalamic nuclei and to three types of stimuli applied to its receptive field: a) graded 5-s temperature shifts at a rate of 9 degrees C/s from 35 degrees C to final temperatures of 20-52 degrees C, generated by a contact thermode; b) graded intensities of electrical stimulation to determine the conduction velocities of converging primary afferent fiber populations; and c) mechanical stimulation ranging from light touch to pinch with serrated forceps. 2. This analysis yielded five classes of units distinguished by the range of responses to mechanical stimuli and by the convergence of different primary afferent fiber populations. These five classes were found among both trigeminothalamic neurons and neurons which could not be antidromically activated. Class 1 units exhibited rapidly adapting responses to hair movement or light touch and received only A-beta primary afferent input. Class 2 units responded to light touch and pressure with maintained discharges and received A-beta primary afferent input. Class 3 units responded maximally to pinch with serrated forceps but also were activated by light touch and pressure. They received A-beta, A-delta, and C fiber input. Class 4 units responded to firm pressure and maximally to pinch with serrated forceps. These units had A-delta and sometimes C fiber input. Class 5 units responded only to pinch with serrated forceps and had exclusive A-delta fiber input. Some cells in all five classes responded antidromically to stimulation of the thalamus. Antidromic action-potential latencies of classes 1,2, and 3 units were shorter than those of classes 4 and 5 units (P less than 0.001). Receptive-field sizes were usually small (1-2 cm2) for classes 1, 2, 4, and 5 units, and larger for class 3 units (one to three trigeminal divisions). The marginal layer of nucleus caudalis contained mostly classes 4 and 5 units, some class 3 units, but no classes 1 or 2 units. The superficial portion of the magnocellular layer contained mostly classes 1 and 2 units, while neurons at the base of this layer contained class 3 units and some classes 4 and 5 units. Cells in the sujacent reticular formation included all 5 classes but showed a tendency to have large receptive fields (greater than 1 trigeminal division). 3. Neurons responding to noxious thermal stimuli (44-52 degrees C) were classes 3 or 4 units. The response patterns of classes 3 and 4 units to noxious thermal stimuli were similar. No classes 1 or 2 units and only one class 5 unit responded to increases in skin temperature. Thermal thresholds ranged from 38 to 50 degrees C and most heat-responsive units responded monotonically to temperatures between 45 and 52 degrees C...