GABA(A) and 5-HT(3) receptors are involved in dorsal root reflexes: possible role in periaqueductal gray descending inhibition.

The dorsal root reflex (DRR) is a measure of the central excitability of presynaptic inhibitory circuits in the spinal cord. Activation of the periaqueductal gray (PAG), a center for descending inhibition of spinal cord nociceptive transmission, induces release of variety of neurotransmitters in the spinal cord, including GABA and serotonin (5-HT). GABA has been shown to be involved in generation of DRRs. In this study, pharmacological agents that influence DRRs and their possible mechanisms were investigated. DRRs were recorded in anesthetized rats from filaments teased from the cut central stump of the left L(4) or L(5) dorsal root, using a monopolar recording electrode. Stimulating electrodes were placed either on the left sciatic nerve or transcutaneously in the left foot. Animals were paralyzed and maintained by artificial ventilation. Drugs were applied topically to the spinal cord. A total of 64 units were recorded in 34 Sprague-Dawley rats. Peripheral receptive fields were found for nine of these units. In these units, DRRs were evoked by brush, pressure, and pinch stimuli. Nine units were tested for an effect of electrical stimulation in the periaqueductal gray on the DRRs. In eight cases, DRR responses were enhanced following PAG stimulation. The background activity was 4.2 +/- 1.9 spikes/s (mean +/- SE; range: 0-97.7; n = 57). The responses to agents applied to the spinal cord were (in spikes/s): artificial cerebrospinal fluid, 7.1 +/- 3.6 (range: 0-86.9; n = 25); 0.1 mM GABA, 16.8 +/- 8.7 (range: 0-191.0; n = 22); 1.0 mM GABA, 116.0 +/- 26.5 (range: 0.05-1001.2; n = 50); and 1.0 mM phenylbiguanide (PBG), 68.1 +/- 25.3 (range: 0-1,073.0; n = 49). Bicuculline (0.5 mM, n = 27) and ondansetron (1.0 mM, n = 10) blocked the GABA and PBG effects, respectively (P < 0.05). Significant cross blockade was also observed. It is concluded that GABA(A) receptors are likely to play a key role in the generation of DRRs, but that 5-HT(3) receptors may also contribute. DRRs can be modulated by supraspinal mechanisms through descending systems.

Response properties and organization of nociceptive neurons in area 1 of monkey primary somatosensory cortex.

The organization and response properties of nociceptive neurons in area 1 of the primary somatosensory cortex (SI) of anesthetized monkeys were examined. The receptive fields of nociceptive neurons were classified as either wide-dynamic-range (WDR) neurons that were preferentially responsive to noxious mechanical stimulation, or nociceptive specific (NS) that were responsive to only noxious stimuli. The cortical locations and the responses of the two classes of neurons were compared. An examination of the neuronal stimulus-response functions obtained during noxious thermal stimulation of the glabrous skin of the foot or the hand indicated that WDR neurons exhibited significantly greater sensitivity to noxious thermal stimuli than did NS neurons. The receptive fields of WDR neurons were significantly larger than the receptive fields of NS neurons. Nociceptive SI neurons were somatotopically organized. Nociceptive neurons with receptive fields on the foot were located more medial in area 1 of SI than those with receptive fields on the hand. In the foot representation, the recording sites of nociceptive neurons were near the boundary between areas 3b and 1, whereas in the hand area, there was a tendency for them to be located more caudal in area 1. The majority of nociceptive neurons were located in the middle layers (III and IV) of area 1. The fact that nociceptive neurons were not evenly distributed across the layers of area 1 suggested that columns of nociceptive neurons probably do not exist in the somatosensory cortex. In electrode tracks where nociceptive neurons were found, approximately half of all subsequently isolated neurons were also classified as nociceptive. Low-threshold mechanoreceptive (LTM) neurons were intermingled with nociceptive neurons. Both WDR and NS neurons were found in close proximity to one another. In instances where the receptive field shifted, subsequently isolated cells were also classified as nociceptive. These data suggest that nociceptive neurons in area 1 of SI are organized in vertically orientated aggregations or clusters in layers III and IV.

The cortical representation of pain.

Anatomical and physiological studies in animals, as well as functional imaging studies in humans have shown that multiple cortical areas are activated by painful stimuli. The view that pain is perceived only as a result of thalamic processing has, therefore, been abandoned, and has been replaced by the question of what functions can be assigned to individual cortical areas. The following cortical areas have been shown to be involved in the processing of painful stimuli: primary somatosensory cortex, secondary somatosensory cortex and its vicinity in the parietal operculum, insula, anterior cingulate cortex and prefrontal cortex. These areas probably process different aspects of pain in parallel. Previous psychophysical research has emphasized the importance of separating pain experience into sensory-discriminative and affective-motivational components. The sensory-discriminative component of pain can be considered a sensory modality similar to vision or olfaction; it becomes more and more evident that it is subserved by its own apparatus up to the cortical level. The affective-motivational component is close to what may be considered 'suffering from pain'; it is clearly related to aspects of emotion, arousal and the programming of behaviour. This dichotomy, however, has turned out to be too simple to explain the functional significance of nociceptive cortical networks. Recent progress in imaging technology has, therefore, provided a new impetus to study the multiple dimensions of pain.

Spinal kappa1 and kappa2 opioid binding sites in rats, guinea pigs, monkeys and humans.

Several lines of work demonstrate that there are two subtypes of kappa opioid receptors. Intrathecally administered agonists for the kappa1 subtype are not effective in treating pain, whereas agonists for the kappa2 receptor are anti-hyperalgesic and anti-allodynic. The question addressed here was whether the ratio of spinal kappa1 to kappa2 receptors was conserved across species. Thus, binding experiments were performed on spinal cord membranes from rats, guinea pigs, monkeys and humans. We found that kappa2 receptors were approximately ten times more abundant than kappa1 receptors in all species tested. This suggests that the anti-hyperalgesic and anti-allodynic properties of kappa2 agonists may also be conserved. Therefore, selective kappa2 agonists may be effective in treating chronic pain in humans.

Multiple effects of morphine on facial scratching in monkeys.

The medullary dorsal horn (MDH), the medullary homolog of the spinal dorsal horn, is a site where opioid-receptor agonists can act at opioid receptors to produce pronounced facial scratching, the behavioral correlate of pruritus. In the present study, after a 10-min baseline period, morphine (5.0 micrograms) was micro-injected into the MDH of monkeys. Behavior was videotaped and facial scratches were counted by two independent raters. Morphine greatly increased facial scratching behavior, which is consistent with previous findings where mu-opioid receptor agonists microinjected into the MDH have been to induce dose-dependent, naloxone-reversible facial scratching in monkeys. In the current research, intramuscular (IM) administration of the opioid-receptor antagonist, naloxone (0.5 mg/kg), reversed this MDH morphine-induced scratching. Additionally, IM morphine (1.0 mg/kg) produced a substantial reduction in facial scratching behavior. Scratching behavior continued at a high rate after injection of saline (0.1 mL/kg, IM). These findings support the hypothesis that morphine has both pruragenic and antipruragenic activity, depending on the site of action.

The medullary dorsal horn. A site of action of morphine in producing facial scratching in monkeys.

BACKGROUND: Pruritus is a common side effect of epidural and intrathecal morphine administration in humans. This naloxone-reversible pruritus is typically present on the trunk, but is often severe around the eyes and nose, of the patients. The brain stem has been proposed as the site where opioids act to produce this effect. The authors studied the effect of morphine administered into the medullary dorsal horn (MDH), the brain stem homologue of the spinal dorsal horn, on facial-scratching behavior in monkeys. METHODS: Morphine was unilaterally microinjected into the MDH of rhesus monkeys. Systemic injections of the opioid-receptor antagonist naloxone (0.5 mg/kg intramuscularly) were also made in combination with morphine microinjection. Systemic injections of the antihistamine chlorcyclizine (1.0 and 2.5 mg/kg intramuscularly) were also made to determine if facial scratching was mediated through histamine release. The monkeys were videotaped for 10-15 min before and 1-2 h after opioid microinjection, and the number and location of scratches were counted. RESULTS: A dose-response curve was established for the mu/delta-opioid-receptor agonist morphine (0.5, 1.0, 2.5, and 5.0 micrograms). Specificity of the site of action within the MDH was examined by systematically changing the microinjection site, and examining the area of the face that the monkeys scratched. Morphine produced large dose-dependent increases in facial scratching ipsilateral to the microinjection. Increases in facial scratching were also observed contralateral to the microinjections. These effects were reversed by naloxone. The facial area scratched after microinjection of morphine was directly related to the injection site, with 1-mm changes in the location of the microinjection resulting in pronounced changes in the area of the face that the monkeys scratched. Systemic injection of chlorcyclizine produced only a small, transient attenuation of morphine's effect. CONCLUSIONS: Data from this study demonstrate that the MDH is a site where morphine acts to produce facial scratching in monkeys by acting at opioid receptors. It is also likely that the MDH is a site where centrally administered opioids act in producing facial pruritus in humans. The effects of morphine on facial-scratching behavior were only modestly attenuated with chlorcyclizine, indicating a minor involvement of a histamine-dependent mechanism of action.

Effects of central administration of opioids on facial scratching in monkeys.

Epidural and intrathecal administration of opioids to humans can produce facial pruritus and scratching that is naloxone reversible. It has been proposed that opioids may act at the level of the medulla to produce facial pruritus and associated scratching behavior. We investigated the effects of mu, delta and kappa opioid-receptor agonists microinjected unilaterally into the medullary dorsal horn (MDH) on facial scratching in cynomolgus monkeys. The selective mu opioid-receptor agonist, DAMGO (3.1-25.0 ng) produced large dose-dependent, naloxone-reversible increases in facial scratches. The selective delta opioid-receptor agonist, DPDPE (1.0-5.0 micrograms) and the selective kappa opioid-receptor agonist, U-50,488H (0.1-5.0 micrograms) did not produce significant increases in facial scratching behavior. We conclude that the MDH is a site where DAMGO, a mu opioid-receptor agonist, can act to produce facial scratching in monkeys, and that the MDH is likely the site where centrally administered opioids act to produce facial pruritus in humans.

Diencephalic projections from the superficial and deep laminae of the medullary dorsal horn in the rat.

An important function of the medullary dorsal horn (MDH) is the relay of nociceptive information from the face and mouth to higher centers of the central nervous system. We studied the central projection pattern of axons arising from the MDH by examining the axonal transport of Phaseolus vulgaris-leucoagglutinin (PHA-L). Labeled axon and axon terminal distributions arising from the MDH were analyzed at the light microscopic level. After large injections of PHA-L into both superficial and deep laminae of the MDH in the rat, labeled axons were observed in the nucleus submedius of the thalamus (SUB), ventroposterior thalamic nucleus medialis (VPM), ventroposterior thalamic nucleus parvicellularis (VPPC), posterior thalamic nuclei (PO), zona incerta (ZI), lateral hypothalamic nucleus (LH), and posterior hypothalamic nucleus (PH). Restriction of PHA-L into only the superficial laminae resulted in heavy axon and varicosity labeling in the SUB, VPM, PO, and VPPC and light labeling in LH. In contrast, after injections into deep laminae, labeled axons were mainly distributed in ZI and PH; some were also in VPM and LH, and fewer still in PO and SUB. Varicosities in VPM, SUB, and PO were significantly larger than those in VPPC, ZI, LH, and PH. Varicosity density was highest in SUB and lowest in the VPPC. We concluded that there are two distinct nociceptive pathways, one originating from the superficial MDH and terminating primarily in the dorsal diencephalon and the second originating from deep laminae of the MDH and terminating primarily in the ventral diencephalon. We propose that in the rat, input from the deeper laminae is primarily involved in the motivational-affective component of pain, whereas input from the superficial MDH is related to both the sensory-discriminative and motivational-affective component of pain.

Responses of neurons in ventroposterolateral nucleus of primate thalamus to urinary bladder distension.

The purpose of this study was to examine effects of a noxious visceral stimulus, urinary bladder distension (UBD), on cells in the ventroposterolateral (VPL) nucleus of anesthetized monkeys. We hypothesized that processing of visceral information in the VPL nucleus of the thalamus is similar to spinothalamic tract (STT) organization of visceral afferent input. Urinary bladder distension excites sacral and upper-lumbar STT cells that have somatic input from proximal somatic fields; whereas, thoracic STT cells are inhibited by UBD. Extracellular action potentials of 67 neurons were recorded in VPL nucleus. Urinary bladder distension excited 22 cells, inhibited 9 cells, and did not affect activity of 36 cells. Seventeen of 22 cells excited by UBD also received convergent somatic input from noxious squeeze of the hip, groin, or perineal regions. No cells activated only by innocuous somatic stimuli were excited by UBD. Five of 9 cells inhibited by UBD had upper-body somatic fields. There was a significant tendency for VPL neurons excited by UBD to have proximal lower-body somatic fields that were excited by noxious stimulation of skin and underlying muscle (P less than 0.001). Antidromic activation of 4 thalamic neurons affected by UBD showed that visceral input stimulated by UBD reached the primary somatosensory (SI) cortex.

Responses of nociceptive SI neurons in monkeys and pain sensation in humans elicited by noxious thermal stimulation: effect of interstimulus interval.

1. Twenty-six nociceptive neurons in the primary somatosensory cortex (SI) of anesthetized monkeys were responsive to noxious thermal stimulation applied to the face. Thermode temperature increased from a base line of 38 degrees C to temperatures ranging from 44 to 49 degrees C (T1). After a period of 5 s, the temperature increased an additional 1 degree C (T2). The neuronal responses to noxious thermal stimuli were compared when the interstimulus interval (ISI) was 30 or 180 s. 2. A linear regression analysis was applied to the stimulus-response functions of neuronal responses to T1 stimuli obtained at ISIs of 180 s. Based on the slopes and linear regression coefficients of these stimulus-response functions, two populations of nociceptive neurons were identified. The neuronal responses of one population of nociceptive SI neurons (WDR1) to T1 stimuli were characterized by steep slopes and high regression coefficients, whereas the other population (WDR2) had flatter slopes and lower regression coefficients. WDR1 neurons responded with monotonic increases in neuronal activity as the stimulus intensity increased. However, the peak frequency of WDR2 neurons often reached a plateau below 47 degrees C. Both WDR1 and WDR2 neurons had receptive fields that encompassed one or two divisions of the trigeminal nerve. 3. The T1 neuronal responses of WDR1 neurons were significantly suppressed when thermal stimuli were delivered with ISIs of 30 s. The T1 neuronal responses of WDR2 and the T2 responses of both WDR1 and WDR2 neurons were not significantly different when ISIs of 30 and 180 s were used. The T1 thresholds of WDR1 and WDR2 neurons were significantly higher when stimuli were delivered with ISIs of 30 s compared with ISIs of 180 s. 4. Most nociceptive SI neurons were located in layers III and IV of area 1-2. In a number of instances, multiple nociceptive neurons were found in the same microelectrode penetration. 5. The humans' intensity of pain sensation paralleled the neuronal responses of nociceptive SI neurons. With the use of a similar paradigm as in the monkey experiments, increases in T1 and T2 temperatures resulted in monotonic increases in pain ratings and change in pain sensation, respectively. However, the intensity of pain sensation to T1 temperatures was suppressed by ISIs of 30 s. Neither ISI produced statistically significant changes in the intensity of pain sensation to T2 stimuli. 6. These data demonstrate that manipulations that alter the intensity of pain sensation also produce concomitant changes in the responsiveness of nociceptive SI neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

The detection and perceived intensity of noxious thermal stimuli in monkey and in human.

1. The magnitude of the sensations produced by small increases in thermal stimuli superimposed on noxious levels of heat stimulation was studied by the use of a simple reaction-time task. Noxious thermal stimuli were presented on the face of three monkeys, the forearm volar surface of three monkeys, and the face of four human subjects. The subject, either monkey or human, initiated a trial by pressing an illuminated button. Subsequently, a contact thermode increased in temperature from a base line of 38 degree C to temperatures of 44, 45, 46, or 47 degrees C (T1). After a variable time period lasting between 4 and 10 s, the thermode temperature increased an additional 0.1, 0.2, 0.4, 0.6, or 0.8 degrees C (T2). The subject was required to release the button as soon as the T2 stimulus was detected. Detection latency, expressed as its reciprocal, detection speed, was defined as the time interval between the onset of T2 and the release of the button. 2. The monkeys' detection speed to stimuli presented on the upper lip was dependent on the intensity of both T1 and T2. Increases in the intensity of T2 between 0.1 and 0.8 degrees C produced faster detection speeds. In general, as the intensity of T1 increased, the detection speed increased to identical T2 stimuli. The monkeys' T2-detection threshold was also dependent on the intensity of T1. 3. The psychophysical functions obtained from stimulation of the monkey's face were compared with those obtained from the volar surface of the monkey's forearm. Whereas the T2 thresholds obtained from stimulation of the monkey's forearm and face were similar, the psychophysical functions obtained from stimulation of the face were significantly steeper than those obtained from stimulation of the forearm. 4. The humans' detection speed of T2 stimuli presented on the face was monotonically related to the intensity of T2 and was dependent on the level of T1. The psychophysical functions obtained from the human's face were equivalent to those obtained from the monkey's faces. 5. A cross-modality matching procedure was used to examine the perceived intensity of pain sensation produced by T2 stimuli in human subjects. The magnitude estimates of these stimuli were dependent on the level of T1, as well as the intensity of T2. Detection speed, plotted as a function of the estimated magnitude of pain, independent of T1 and T2 temperature, was best fit by a logarithmic function.(ABSTRACT TRUNCATED AT 400 WORDS)

Responses of monkey medullary dorsal horn neurons during the detection of noxious heat stimuli.

1. We examined the activity of thermally sensitive trigeminothalamic neurons and nonprojection neurons in the medullary dorsal horn (trigeminal nucleus caudalis) in three monkeys performing thermal and visual detection tasks. 2. An examination of neuronal stimulus-response functions, obtained during thermal-detection tasks in which noxious heat stimuli were applied to the face, indicated that wide-dynamic-range neurons (WDR, responsive to innocuous mechanical stimuli with greater responses to noxious mechanical stimuli) could be subclassified based on the slope values of linear regression lines. WDR1 neurons exhibited significantly greater sensitivity to noxious heat stimulation than WDR2 neurons or nociceptive-specific neurons (NS, responsive only to noxious stimuli). 3. In one behavioral task, the monkeys detected 1.0 degrees C increases in noxious heat from preceding noxious heat stimuli ranging from 44 to 48 degrees C. WDR1, WDR2, and NS neurons increased their discharge frequency as a function of the intensity of the first noxious heat temperature (T1) as well as the final temperature (T2). The responses of WDR1 neurons were greater than those produced by WDR2 or NS neurons across all the temperatures examined. The order of stimulus presentation affected the responses of WDR1 neurons to 1.0 degrees C increases in the noxious heat range but not those of WDR2 or NS neurons. 4. In a second behavioral task, the monkeys detected small increases in noxious heat (0.2-0.8 degrees C) from a first temperature of 46 degrees C. Although the responses of all three classes of neurons were monotonically related to stimulus intensity, WDR1 neurons exhibited greater sensitivity to small temperature increases than either WDR2 or NS neurons. 5. Subpopulations of all three classes of neurons exhibited responses that were independent of thermal stimulus parameters or sensory modality and that only occurred during the behavioral task. These task-related responses were time-locked to specific behavioral events associated with trial initiation and trial continuation. 6. These data provide evidence that a subpopulation of WDR neurons is the dorsal horn cell type most sensitive to small increases in noxious heat in the 45-49 degrees C temperature range and provides the most information about stimulus intensity. The findings support the view that nociceptive neurons have the capacity to precisely encode stimulus features in the noxious range and that WDR neurons are likely to participate in the monkeys' ability to perceive the intensity of such stimuli.

The correlation of monkey medullary dorsal horn neuronal activity and the perceived intensity of noxious heat stimuli.

1. We examined the relationship between the activity of medullary dorsal horn nociceptive neurons and the monkeys' ability to detect noxious heat stimuli. In two different detection tasks, the temperature of a contact thermode positioned on the monkey's face increased from 38 degrees C to temperatures between 44 and 48 degrees C (T1). After a variable time period, the thermode temperature increased an additional 0.2-1.5 degrees C (T2), and the monkeys' detection speed from the onset of T2 was determined. We previously have established that detection speed is a measure of the perceived intensity of noxious thermal stimuli. Nociceptive neurons were classified as wide-dynamic-range (WDR, responsive to innocuous mechanical stimuli with greater responses to noxious mechanical stimuli) and nociceptive-specific (NS, responsive only to noxious stimuli). WDR neurons were subclassified as WDR1 and WDR2 based on the higher slope values of the stimulus-response functions of WDR1 neurons. The monkeys were trained to detect small increases in noxious heat, and their detection speeds were correlated with the responses of WDR1, WDR2, and NS neurons. 2. Detection speeds to T2 temperatures of 1.0 degrees C from preceding T1 temperatures of 45 and 46 degrees C were faster during a preceding ascending series of stimuli than during a descending series. Similarly, the peak discharge frequencies of WDR1 neurons in response to the same stimuli were greater during the ascending series of T2 temperatures. In contrast, the responses of WDR2 and NS neurons showed no significant differences during the ascending and descending series of stimuli. 3. Detection speeds following 0.4, 0.6, and 0.8 degrees C T2 stimuli were higher when the preceding T1 temperature was 46 degrees C as compared with detection speeds to the identical stimuli when the preceding T1 temperature was 45 degrees C. WDR1 neurons also exhibited a significant increase in peak discharge frequency to these same T2 stimuli when the preceding T1 temperature was 46 degrees C. In contrast, the neuronal activity of WDR2 and NS neurons did not differ on 45 and 46 degrees C T1 trials. 4. The relationship between detection speed and neuronal peak discharge frequency was examined in response to different pairs of T1 and T2 stimuli when T1 was either 45 or 46 degrees C. There was a significant correlation between detection speed and neuronal discharge for WDR1 and WDR2 neurons. No correlation was observed for NS neurons. 5. The magnitude of neuronal activity on correctly detected and nondetected trials was compared when T1 was 46 degrees C and T2 was 0.2 degree C.(ABSTRACT TRUNCATED AT 400 WORDS)

Distribution and size of GABAergic neurons in area 7b and the retroinsular cortex of the monkey.

The distribution of gamma-aminobutyric acid (GABA) neurons was examined in the retroinsular cortex (Ri) and area 7b of the monkey. GABA-immunoreactive somata and puncta were observed in all layers of Ri and area 7b. The densest concentration of these neurons was located in layers I and II. The vast majority (98.9%) of GABA-immunoreactive somata were less than 15 microns in major diameter. These data demonstrate that high concentrations of GABAergic neurons are located in those cortical layers that have been shown to receive afferent projections from corticocortical fibers.

Distribution of GAD-immunoreactive neurons in the first (SI) and second (SII) somatosensory cortex of the monkey.

The distribution of neurons immunoreactive for glutamic acid decarboxylase (GAD), the synthesizing enzyme of gamma-aminobutyric acid (GABA), was examined in the first (SI) and second (SII) somatosensory cortex of monkeys. GAD-like immunoreactive (GAD-LI) somata and puncta were present in all layers of SI and SII. All GAD-LI somata were identified as non-pyramidal neurons and were most numerous in layer IV of SI and in layer III of SII. Layer IV of SI also contained the highest density of GAD-LI puncta. In SII, GAD-LI puncta were distributed more homogeneously and did not show a dense band of labelled puncta in layer IV. The major and minor diameters of GAD-LI somata in SII ranged from 6.9 to 26.2 micron and from 6.2 to 19.0 micron, respectively. The major diameters of GAD-LI somata in SII were significantly smaller than those in SI in layers I, III and IV. Differences between the distributions of GAD-LI puncta and somata in SI and SII may be accounted for by differences in the number and/or distribution of different types of GABAergic neurons. Functional differences of neurons in SI and SII may be related to the differences in GABAergic inhibitory mechanisms and reflected in the distribution of GABAergic neurons.

SI nociceptive neurons participate in the encoding process by which monkeys perceive the intensity of noxious thermal stimulation.

The activity of primary somatosensory (SI) cortical nociceptive neurons was recorded while the monkeys performed a psychophysical task in which they detected small increases in skin temperature superimposed on noxious levels of thermal stimulation. The detection latency to these stimuli, expressed as detection speed, was used as a measure of the perceived intensity of sensation. Two-thirds of the neurons that responded to noxious thermal stimulation increased their discharge in response to graded increases in stimulus intensity. The remaining neurons responded to noxious thermal stimulation, but did not grade their response with the intensity of the stimulus. The response of SI nociceptive neurons that encode the intensity of noxious thermal stimulation was significantly correlated with the monkey's detection speed. We conclude that SI nociceptive neurons are involved in the encoding process by which monkeys perceive the intensity of noxious thermal stimulation.

The recovery of sensory function following skin flaps in humans.

Two cross-sectional studies were made of the recovery of tactile and pain sensitivity in subjects having skin flaps in the region of the chest and neck as a result of tumor excision. In experiment 1, stimuli ranging from 2.46 to 17.10 gm of force were delivered by von Frey hairs to the flaps and comparable normal sites in 35 subjects at times ranging from 1 month to 10 years after surgery. No subjects perceived stimuli of less than 11.80 gm, thermal, or moving touch applied to flaps, whereas 21 percent perceived 11.80 gm or greater force (judged as painful applied to normal skin). The results of experiment 2 showed that these findings were not due to visual information available to subjects. Possible explanations for the fact that these results are radically different from those reported in the literature are discussed.

Somesthetic sensitivity in young and elderly humans.

Absolute thresholds were measured on 27 young (ages 19 to 31) and 21 elderly (ages 55 to 84) humans to six modes of cutaneous stimulation (single ramp-and-hold skin indentations--tactile, vibration at 40 and 250 Hz, temperature increases and decreases, and noxious heat) at two sites, the thenar eminence and the plantar foot. Comparisons of the elderly and young groups showed that elderly persons were significantly, p less than or equal to .001, less sensitive than young individuals to mechanical stimuli (tactile and vibration) at both sites. No significant differences were found in thresholds to thermal stimuli (warm-, cold-, and heat-pain) at either site except elderly feet were significantly, p less than or equal to .001, less sensitive than young feet to warm stimuli. Thresholds of elderly individuals were compared with the young group thresholds for deficits in sensitivity. All elderly participants showed deficits to one or more of the stimulus modes at one or the other site. There were significantly, p less than or equal to 0.01, more deficits to mechanical than to thermal stimuli. There was no increase in the frequency of deficits with increasing age.

The medullary dorsal horn: a target for the expression of opiate effects on the perceived intensity of noxious heat.

We examined the effects of morphine microinjected into the medullary dorsal horn (MDH) on the ability of monkeys to detect temperature increases in the noxious heat range. Behavioral detection latency and the percentage of correct detections were used as measures of the perceived intensity of noxious heat stimuli. Three monkeys were trained to detect a change (T2) of 0.4, 0.6, or 1.0 degrees C from a previous noxious heat level of 46 degrees C (T1). Effects on attentional, motivational, and motoric aspects of the monkeys' behavior were assessed by having them detect innocuous cooling and visual stimuli in tasks of similar difficulty. Morphine (1, 3, and 10 micrograms) microinjected into the MDH produced a dose-dependent and stimulus-intensity-dependent increase in the latency to detection of the T2 stimuli. These effects were opiate receptor-mediated since they were antagonized by systemically administered naloxone (0.5 mg/kg, i.m.) given 40 min after the microinjection of morphine. There were no effects of morphine on the behavioral detection latencies to the innocuous cooling and visual stimuli, indicating that the effects of morphine were modality-specific and independent of changes in motivation, attention, or motoric ability. These data demonstrate a pharmacologically specific effect of opiates on the perceived intensity of noxious heat stimuli at the earliest central relay pathway transmitting noxious information.

Wide-dynamic-range dorsal horn neurons participate in the encoding process by which monkeys perceive the intensity of noxious heat stimuli.

The role of dorsal horn wide-dynamic-range (WDR) and nociceptive-specific (NS) neurons in the encoding of the perceived intensity of noxious stimuli was determined while monkeys detected near-threshold changes in the intensity of noxious heat stimuli. Behavioral detection latencies were a reliable measure of the perceived intensity of these stimuli. There was a significant correlation between behavioral detection latency and neuronal discharge of WDR, but not NS neurons. In addition, WDR neurons exhibited greater activity on correctly detected vs non-detected trials, whereas NS neurons did not. We conclude that WDR neurons are involved in the encoding process by which monkeys perceive the intensity of noxious heat stimuli near detection threshold.