Morphine analgesia potentiated but tolerance not affected by active immunization against cholecystokinin.

Administration of cholecystokinin was recently found to attenuate opiate analgesia. In the present study, the role of endogenous cholecystokinin in opiate analgesia was examined. Endogenously released cholecystokinin was sequestered by antibodies to cholecystokinin developed in response to an active immunization procedure. Morphine analgesia was potentiated and prolonged in rats immunized against cholecystokinin. The rate of development of morphine tolerance, however, was not affected by the antibodies. Endogenous cholecystokinin appears to function as a short-term modulator of opiate action.

The twitch in horses: a variant of acupuncture.

The twitch procedure in horses attenuates the increase in the heart rate evoked by pain-inducing stimuli and the reaction of the animals to such stimuli. Endorphin systems are probably involved in the effectiveness of the twitch, since its action is blocked by naloxone and its application increases plasma concentrations of immunoreactive beta-endorphin. The mode of action of the twitch cannot be explained by the generally accepted theory of divertive pain and may resemble that of classical acupuncture.

The ascending projections of the dorsolateral funiculus of the spinal cord in the primate.

The ascending projections of the dorsolateral funiculus of the spinal cord to the brain stem have been determined in five macaque monkeys. Connections to the lateral cervical nucleus and to the reticular nucleus of the cord in the C1 and C2 segments are present. In the medulla the most prominent connections are to the nuclei "Z" and "x" of Brodal and Pompeiano, to the rostral portion of n. gracilis and to the n. proprius of the restiform body. Minor projections reach the rostral part of the medial and lateral cuneate nuclei, the reticular nucleus, the n. centralis dorsalis and the periependymal gray. There were no projections to planes rostral to the medulla. In view of the connections established it is concluded that ascending systems in the DLF to the brain stem of primates are concerned with transmission of mechanoreceptor input to the cerebellum and thalamus and that nociceptive relay appears very unlikely.

Cerebral responses to electrical tooth pulp stimulation in man. An objective correlate of acute experimental pain.

The pulp of individual teeth of 17 normal adult volunteers was electrically stimulated via pairs of electrodes implanted into dentine. Computer-summated responses recorded from the surface of the head were composed of two concurrent sequences of events, one of which was seen maximally over midline areas and the other over the lower portions of the postcentral regions. Appropriate tests demonstrated that these wave forms represented cerebral tooth pulp-evoked potentials. Because tooth pulp-evoked potentials represent objective, quantifiable, nonverbal concomitants of central events associated with the perception of noxious stimuli, they may prove helpful in investigating acute experimental pain in man.

The accuracy of remembering chronic pain.

Twelve chronic pain patients were employed in an investigation of the accuracy of memory for chronic pain. Subjects first made pain ratings before entering a treatment program. At dismissal 3-11 weeks later they were asked to remember how much pain they had had at baseline. Results show that patients remembered having significantly more pain than they actually rated during the baseline period. Caution is therefore warranted when using post-hoc pain measures with chronic pain patients.

Analgesia after lesions of nucleus reticularis magnocellularis: differential effect on supraspinal versus spinal pain reflexes.

The present studies examine the effect of bilateral electrolytic lesions of descending fibers arising from nucleus reticularis magnocellularis (NMC) on responding to noxious peripheral thermal or mechanical stimulation and on spinal cord monoamine levels. The lesion effects were quantified by examining two supraspinally organized pain responses, the hot plate latency and vocalization threshold and two spinally organized nociceptive reflexes, tail flick latency and hind limb flexion threshold. Following interruption of descending NMC fibers, a profound analgesia was observed on supraspinally organized pain responses. Assay of spinal cord serotonin (5-HT) indicated that the NMC lesions also destroyed appreciable numbers of descending 5-HT fibers of passage originating in nucleus raphe magnus (RM). A modest hypersensitivity to pain occurred after control lesions in RM suggesting that the analgesia observed after NMC lesions would have been even more pronounced if RM fibers of passage had not been concomitantly destroyed. To assess whether the analgesia observed after NMC lesions was due to non-specific destruction of a given volume of reticular tissue, control lesions were placed in nucleus subcoeruleus (NSC). NSC lesions resulted in a hypersensitivity to pain and significant depletion of spinal cord noradrenaline (NA). These data suggest both that the analgesia observed after NMC lesions was not due to non-specific destruction of the reticular formation, and that descending NSC NA fibers tonically suppress pain. The above analgesic effects were observed exclusively on supraspinally organized pain responses, not spinally organized nociceptive reflexes. This supported previous studies demonstrating differential descending control of nociception in the spinal versus intact preparations. In summary, the present data suggest that descending NMC fibers tonically suppress ascending pain transmission.

Controllability, coping behavior, and stress-induced analgesia in the rat.

Exposure to painful or stressful stimuli produces an analgesic reaction which can persist for 1-2 h post-stress. In the typical stress-induced analgesia study the subject is not permitted to alter or exert control over the aversive event to which it is exposed. That is, its behavior affects neither the duration or intensity of the event. The experiments reported here attempted to determine whether this inability of the subject to control the aversive event is an important determinant of stress-induced analgesia, or whether simple exposure to painful events is a sufficient condition for its production. In the first experiment rats were given either escapable electric shocks (the subject's behavior could terminate the shock), equal amounts of inescapable shock, or no shock. Tail-flick to radiant heat was assessed 30 min later. The group given inescapable shock was strongly analgesic, while the group given an equal amount of escapable shock was only mildly analgesic. Thus the controllability of the shock or the availability of a coping response determined the antinociceptive reaction which followed. The second experiment revealed that this differential effect of controllability on tail-flick responding is masked, shortly after the end of the shock session, by a transient analgesic effect of shock which is not sensitive to the controllability dimension. The implications of these results for stress-induced analgesia and the activation of opioid systems are discussed.

Psychophysical assessment of tactile, pain and thermal sensory functions in burning mouth syndrome.

Tactile, two-point discrimination, thermal change detection and heat pain thresholds as well as oral stereognostic ability, warmth scaling and heat pain tolerance were compared in a group of 72 subjects with burning mouth syndrome (BMS) and 43 age- and sex-matched control subjects. No differences were found between the BMS and control subjects for any of the sensory modalities tested except for heat pain tolerance. Pain tolerance was significantly decreased for the BMS subjects at the tongue tip, a site of clinical pain in approximately 85% of the subjects tested in this study, but not at the cutaneous lower lip which was a site of pain only in approximately 17% of the subjects tested in this study. In addition, no differences in heat pain tolerance were found at the cutaneous lower lip between the control subjects and the BMS subjects who reported pain on the mucosal lower lip (approximately 49% of subjects), but heat pain tolerance was significantly decreased at this site for those BMS subjects tested without pain on the mucosal lower lip (approximately 51% of subjects). These findings do not suggest a psychogenic origin for the alteration of heat pain tolerance in the BMS subjects, but suggest instead specific changes in their peripheral or central sensory functions.

A bioenergetic basis for peripheral nerve fiber dissociation.

The selective vulnerability of myelinated axons in lesions of peripheral nerve is incompletely understood and appears somewhat at variance with the energy conservation attached to saltation in these fibers. We evaluated the relative energy requirement of resting A and C fibers in rabbit vagus nerve by measuring the amplitude of the components of the compound action potential at 5-10 min intervals during incubation in Ringer-bicarbonate solutions containing 0-20 mM glucose. In nerves in which the perineurial sheath was retained intact the A components remained at control amplitude with 20 mM glucose but, after a plateau period, declined increasingly rapidly with 5, 2, 1, 0.5 and 0 mM glucose. 2mM glucose sufficed to maintain control amplitude of the C fiber component. In desheathed nerves the A component remained at control amplitude with 5 mM glucose but declined increasingly rapidly with 2, 1, 0.5 and 0 mM glucose; 0.5 mM glucose sufficed to maintain control amplitude to C fibers. The depressed potentials generally recovered incompletely after transfer to glucose 5 mM (desheathed) or 20 mM (sheathed); however, the partial recovery was more rapid and more nearly complete in the C fiber group than in the A fiber group (P less than 0.05). The data demonstrate that resting A fibers are much more susceptible to energy lack in vitro than resting C fibers. This suggests that deprivation of energy may be a factor in the preferential destruction of large fibers, termed fiber dissociation, which characterized several syndromes of chronic pain.

A spino-reticulo-thalamic pathway in the rat: an anatomical study with reference to pain transmission.

The axonal tract tracing technique using the transport in both the retrograde and orthograde directions of wheat-germ agglutinin conjugated to horseradish peroxidase permitted the observation of both retrogradely labelled spinal neurons and anterogradely labelled thalamic fiber terminals in the same animal after injections of the compound in the nucleus reticularis gigantocellularis, thus allowing the definition of the spino-reticulo-thalamic pathway which relays in this nucleus in the rat. Results of the present study are in favor of the existence of a pathway originating mostly in the spinal ventral horn and ending in the intralaminar nuclei of the thalamus, in particular in the nucleus center median, after a relay in the nucleus reticularis gigantocellularis. Origin and termination of this pathway seem to be well differentiated from those of the direct spino-thalamic tract. The results are discussed with reference to the possible involvement of this pathway in some aspects of pain transmission. It is suggested, in particular, that the direct spino-thalamic system which relays in the thalamic ventrobasal complex, presents the features required of a structure playing a role in the sensory-discriminative aspects of pain transmission; in contrast, the spino-reticulo thalamic system defined here could be involved in some motor and/or behavioral responses related to pain.

Opioid neurons and pain modulation: an ultrastructural analysis of enkephalin in cat superficial dorsal horn.

To clarify the circuitry through which opioid compounds modulate spinal and trigeminal nociceptive transmission, we have examined the synaptic associations formed by leucine-enkephalin-containing (enkephalin) neurons in the superficial dorsal horn of the cat. As described previously, punctate enkephalin immunoreactivity is concentrated in the marginal layer (lamina I) and in both the outer and inner layers of the substantia gelatinosa (lamina IIo and IIi). In colchicine treated cats, enkephalin perikarya are most numerous in lamina I and at the border between laminae I and II. Ultrastructural analysis reveals that enkephalin cells receive a diverse afferent input. The majority of afferent inputs are presynaptic to the enkephalin dendrites; few axosomatic synapses are seen. Among these presynaptic axonal profiles are unlabeled axons which resemble primary afferent terminals, including the characteristic central axonal varicosity. Enkephalin dendrites are also postsynaptic to enkephalin immunoreactive axons. Two types of enkephalin axonal profiles appear in the superficial dorsal horn. Class I profiles are only found in lamina I. These are large profiles which form few synapses; those synapses made are axodendritic. Class II enkephalin axons are smaller and are distributed in both layers I and II. While Class II axons most commonly form axo-dendritic synapses, they also form axo-axonic synapses with flat vesicle-containing profiles; the latter are generally presynaptic to the enkephalin terminals. Serial analysis further revealed that both the enkephalin and the flat vesicle-containing profile synapse onto a common dendrite. Although enkephalin axons frequently lie adjacent to round vesicle-containing profiles, anatomical evidence that opioid axons form synapses with this type of ending was not found. An additional type of enkephalin vesicle containing-profile is found in layer IIi; its morphological features do not clearly distinguish its axonal or dendritic origin. These endings are typically postsynaptic to unlabelled central endings, and provide minimal presynaptic input to other elements in the neuropil. Like some class II axons, these labelled profiles contain vesicles which cluster at the membrane immediately adjacent to unlabelled central axons. These results indicate that spinal enkephalin neurons receive a variety of synaptic inputs. These include inputs which may derive from primary afferent axons. Enkephalin neurons, in turn, influence nociceptive transmission predominantly through postsynaptic mechanisms. Finally, while we did not observe enkephalin terminals presynaptic in an axoaxonic relationship, the possibility that enkephalin neurons modulate the excitability of fine fiber nociceptive and nonnociceptive afferents via "nonsynaptic interactions" is discussed.

Selective averaging of argon laser induced pre-pain and pain related cortical responses.

The argon laser was found to be suitable for pre-pain and pain stimulation. The visible (488 and 515 nm) argon laser light penetrates the skin and is absorbed by melanin and haemoglobin. Argon laser stimuli of different intensities were perceived differently, and could be classified into 3 pre-pain and 3 pain classes. The pre-pain sensations were either perceived as warmth, weak pin prick, or weak pin prick followed by warmth. The pain sensations were perceived as painful pin pricks of different intensities. Single cortical responses to argon laser stimuli were averaged selectively, according to this perceptual classification, and characteristic pre-pain and pain related cortical responses were recorded. The sensation of warmth was related to a late cortical deflection, 700-800 ms after stimulus onset, whereas the pin prick related response appeared with a latency of 300-400 ms. Pre-pain related responses were only recorded when selective averaging according to perception was used. The amplitude of the selectively averaged pain related cortical responses correlated with the subjective sensation of pain. Selective averaging of pre-pain and pain related single responses may prove useful in studying the cortical projection of different perceptions or modality patterns, and to investigate the function of the thermal and nociceptive pathways and their interactions.

Differential effects of persistent nociceptive stimulation on sleep stages.

The purpose of this work was to investigate the sequence of modifications of sleep and pain parameters in a condition of persistent nociceptive stimulation. In freely moving cats carrying implanted electrodes, continuous polygraphic and behavioral recordings were collected 24 h a day for several consecutive days before and after treatment. Injection of formalin (2 ml, 37%) elicited continuous wakefulness (1-6 h) associated with behavioral manifestations of pain. This insomnia was followed by the delayed appearance of LS (light, slow wave sleep) DS (deep slow wave sleep) and REM (rapid eye movement sleep). On days 1 and 2 after injection, pain manifestations displayed a gradual decrease, while total sleep time (LS + DS + REM) slowly returned to normal levels. On day 1, the amount of LS was not modified, but DS and REM were greatly decreased. For 12 h after the first REM episode, REM was decreased while DS was already at the basal levels. Formalin elicited a long-lasting increase in EMG activity of the tibialis anterior muscle which was suppressed during REM and returned to higher levels afterwards. Prolonged wakefulness and delay in sleep stage appearance were also recorded when a 24-h sleep deprivation preceded formalin injection. In this condition, LS, DS and REM amount were at basal levels from their first reappearance, and a rebound in total sleep time and DS occurred on day 2 after the injection. After injection of smaller doses of formalin (0.5 ml, 8%), the amount of LS, DS and REM was at control levels since day 1. The results suggest that (1) the amount of sleep depends on sleep debt and on the level of pain intensity and (2) sleep stages are differentially sensitive to persistent pain.

Behavioral evidence for a crossed ascending pathway for pain transmission in the anterolateral quadrant of the rat spinal cord.

Thresholds of two behavioral responses to noxious pressure of the hindpaws (withdrawal, vocalization) were analyzed before and 3 weeks after a lesion of various quadrants of the spinal cord at the cervical level. The threshold of the spinal reflex could not be modified. Threshold of vocalization elicited by the pressure of one hindpaw was significantly increased when, and only when, the opposite ventrolateral quadrant was cut. These results emphasize the role of the lateral spinothalamic tract in the transmission of noxious messages.

Stimulation-produced and stress-induced analgesia: cross-tolerance between opioid forms.

Electrical stimulation of medial brainstem sites produces potent analgesia in rats that is either opioid- or non-opioid-mediated depending on the specific brain region stimulated. Footshock stress also causes opioid and non-opioid forms of analgesia in rats depending on the exact parameters of footshock administered. We now report that opioid, but not non-opioid, stress analgesia demonstrates cross-tolerance with opioid, but not non-opioid, stimulation-produced analgesia. This finding suggests that opioid forms of stimulation-produced and stress-induced analgesia share a common substrate.

Response properties of spinal neurons projecting to midbrain or midbrain-thalamus in the monkey.

Response and receptive field properties were determined for 24 spinal neurons backfired from midbrain or midbrain-thalamus in the anesthetized monkey. Recording sites were located in laminae I (11 cells), IV (6), V (6) and VI (1) in the lumbosacral spinal cord. The mean axonal conduction velocity of cells projecting to midbrain was significantly less than that of cells projecting to midbrain-thalamus. Cells backfired only from midbrain had complex excitatory receptive fields whereas those projecting to midbrain-thalamus had excitatory receptive fields confined to a single limb. Cells in both populations had complex inhibitory receptive fields.

Role of spinal cord neuropeptides in pain sensitivity and analgesia: thyrotropin releasing hormone and vasopressin.

The existence of a wide variety of neuropeptides within the spinal cord dorsal horn raises the question of their possible roles in sensory processing. The present series of behavioral experiments examined the effects of intrathecal (IT) administration of two such neuropeptides, thyrotropin-releasing hormone (TRH) and vasopressin (VAS), on pain sensitivity and antinociception. TRH exerted no marked effect on basal pain sensitivity over the dose range examined (0.25 ng-2.5 micrograms). However, a U-shaped dose-response effect on morphine antinociception (3 micrograms, IT) was observed, wherein potent attenuation, moderate attenuation, or enhancement of morphine-induced antinociception was observed following the various doses tested. In contrast, VAS produced non-opiate antinociception at the highest doses tested (25 ng and 250 ng) and none of the VAS doses (0.25 ng-250 ng) appeared to interact with IT morphine (3 micrograms) antinociception. Lastly, IT TRH was not observed to interact with IT VAS antinociception. These data provide evidence that these neuropeptides exert strikingly different effects on pain sensitivity and opiate antinociception, and provide initial evidence that TRH may be included in the growing list of neuropeptides that can act like endogenous opiate antagonists within the central nervous system.

A possible pain control system in a non-mammalian vertebrate (a lizard, Gekko gecko).

In a lizard (Gekko gecko) the anterograde tracer PHA-L was microiontophoretically applied to the predominantly serotonergic nucleus raphes inferior. Extensive spinal projections from the rostral magnocellular part of this nucleus were demonstrated to the superficial layers of the dorsal horn and to the intermediate zone, more sparsely to the ventral horn. But, in addition, retrogradely labeled neurons were found in and just below a periventricular cell group in tegmentum mesencephali, i.e. the laminar nucleus of the torus semicircularis, a cell group which receives spinal afferents and projects to the spinal cord as the mammalian periaqueductal gray. These data suggest the presence of a three-tiered pain control system in a lizard composed of projections from the laminar nucleus of the torus semicircularis to the rostral part of the inferior raphe nucleus which in its turn projects to the superficial layers of the dorsal horn of the spinal cord.

Effects of nitrous oxide exposure on Met-enkephalin levels in discrete areas of rat brain.

Rat were exposed to 80% nitrous oxide in oxygen for 1 and 18 h. Met-enkephalin levels in the dorsal raphé, medial thalamus, periaqueductal grey, raphé magnus and locus coeruleus were measured by radioimmunoassay in control and treated animals. There was no change in Met-enkephalin levels at either time point in any of the brain areas examined.

Neural inputs from the uterus to the paraventricular magnocellular neurons in the rat.

Extracellular action potentials were recorded from antidromically identified, tonically firing cells in the hypothalamic paraventricular nucleus (PVN) of ovariectomized, estrogen-treated female rats under urethane anesthesia. Genital or somatic sensory stimuli, or electrical stimulation of the nerves innervating the pelvis were applied. Uterine horn or vaginal distension each excited 33% of the neurons tested. Probing of the cervix had no effect. Hindpaw pinch produced excitation in 39% and inhibition in 11% of the neurons tested. Non-noxious somatic stimuli had no effect. Stimulation of the uterine afferent nerves, the hypogastric and pelvic nerves, excited 55% and 30% of the neurons tested, respectively. Stimulation of a somatic nerve of the hindleg, the sciatic nerve, activated 80% of the neurons tested. These results indicate that specific sensory afferents arrive at the PVN from the uterus; in addition, somatic afferents converge in this hypothalamic nucleus.