Brainstem System Research Articles

Role of basal ganglia–brainstem systems in the control of postural muscle tone and locomotion

This chapter argues that a basal ganglia-brainstem system throughout the mesopontine tegmentum contributes to an automatic control of movement that operates in conjunction with voluntary control processes. Activity of a muscle tone inhibitory system and the locomotion executing system can be steadily balanced by a net excitatory cortical input and a net inhibitory basal ganglia input to these systems. We further propose that dysfunction of the basal ganglia-brainstem system, together with that of the cortico-basal ganglia loop, underlies the pathogenesis of motor disturbances expressed in basal ganglia diseases.

Morphology of the turtle accessory optic system.

Neural signals of the moving visual world are detected by a subclass of retinal ganglion cells that project to the accessory optic system in the vertebrate brainstem. We studied the dendritic morphologies and direction tuning of these brainstem neurons in turtle (Pseudemys scripta elegans) to understand their role in visual processing. Full-field checkerboard patterns were drifted on the contralateral retina while whole-cell recordings were made in the basal optic nucleus in an intact brainstem preparation in vitro. Neurobiotin diffused into the neurons during the recording and was subsequently localized in brain sections. Neuronal morphologies were traced using appropriate computer software to analyze their position in the brainstem. Most labeled neurons were fusiform in shape and had numerous varicosities along their processes. The majority of dendritic trees spread out in a transverse plane perpendicular to the rostrocaudal axis of the nucleus. Neurons near the brainstem surface were often oriented tangential to that surface, whereas more cells at the dorsal side of the nucleus were oriented radial to the brainstem surface. Further analysis of Nissl-stained neurons revealed the largest neurons are located in the rostral and medial portions of the nucleus although neurons are most densely packed in the middle of the nucleus. The preferred directions of the visual responses of the neurons in this sample did not correlate with their morphology and position in the nucleus. Therefore, the morphology of the cells in the turtle accessory optic system appears dependent on its position within the nucleus while its visual responses may depend on the synaptic inputs that contact each cell.

Unity from duality

When, in the primeval sea, creatures first began to crawl, "right" and "left" came into being, yielding neuronal nets to control response to the sidedness of stimuli. In the half billion years of moving and sensing, two brains have evolved, the right and the left; and human experience now shows them to be roughly equivalent, potentially independent, conscious entities. This dramatic fact is evidenced by "split-brain" patients and by numerous cases of therapeutic removal of either hemisphere. Equally dramatic, of course, is that there is not the slightest sign of this duality in everyday experience, the right and left visual fields are seamlessly knit, and cross purpose is absent in the moment to moment operation of the two cerebral hemispheres. This unity is constantly synthesized by the 100,000,000 fibers passing from each hemisphere to the other; the vastness of that interchange emphasized upon comparison with the mere 1,000,000 fibers conveying all the visual world from each eye. With the large distances in the human brain some 100+ ms may commonly transpire for one hemisphere to send to and receive a response from the other. Efficiency thus demands that most neuronal calculation occur within rather than between hemispheres, thereby promoting differences in the characteristic capabilities of each alone, i.e., "hemispheric specialization". Despite this there is a bewildering bilaterality of activation revealed by fMRI for most cognitive tasks. In the absence of the forebrain commissures brainstem systems can be shown, in macaques, also to participate in the unification of behavioral result from the actions of the separated hemispheres. The system favors synthesis from congruent (visual) input to the two hemispheres; but in the face of incompatible hemispheric input, the two hemispheres are able to work out an accommodation in their control of subcortical systems.

Firing of micturition center neurons in the rat mesopontine tegmentum during urinary bladder contraction

Micturition is controlled by a network of brainstem neurons involving the Barrington’s nucleus. To depict clearly the brainstem system for micturition control, the present study was designed to record single neuronal activity in the mesopontine tegmentum including the Barrington’s nucleus, and to observe its precise timing in relation to bladder contraction recorded simultaneously. About 1/5 of neurons encountered had firing modulated in relation to bladder contraction. Three types of neurons were distinguished; those which fired only prior to the start of contraction (type E1), those whose firing started shortly prior to and was maintained during contraction (type E2), and those whose firing was strongly suppressed during contraction (type I). Type E2 neurons were most frequently observed in the Barrington’s nucleus and its close vicinity, while the neurons of the other two types were scattered widely in the mesopontine tegmentum. The results show clearly that direct neural signals to induce bladder contraction may arise from the Barrington’s nucleus, and that the nucleus may receive regulatory inputs from wide areas of the mesopontine tegmentum. In addition, the present study clarified that the noradrenergic and cholinergic neurons, which are located in nuclei adjoining the Barrington’s nucleus and function to control sleep/wakefulness, may not be concerned in controlling micturition directly.

Nitric Oxide Signalling System in Rat Brain Stem: Immunocytochemical Studies

Nitric oxide is a free radical, which is produced in several tissues of the body and is thought to be the first of a new class of neural messenger molecules and a retrograde modulator of synaptic transmission in the brain. Nitric oxide synthase (NOS) is the enzyme that produces nitric oxide from the substrate l-arginine. The pattern of the distribution of neuronal isoform of NOS was investigated in neurones and fibres in the brain stem using standard immunocytochemistry. In our results, NOS positive neurones and processes were seen in the spinal trigeminal nucleus, gracile nucleus, nucleus of the solitary tract, nucleus ambiguus, reticular nuclei and lateral to the pyramidal tract of the medulla. In the pons, heavily labelled NOS containing neurones were seen in the pedunuclopontine tegmental nucleus, ventral tegmental nucleus and in the laterodorsal tegmental nucleus. The localization of neuronal NOS expressing neurones suggests a widespread neuromodulatory role for the nitric oxide in the central nervous system of rat.

Modulation of Ca2+ currents in rat thalamocortical relay neurons by activity and phosphorylation.

Rhythmic low and high frequency activity in thalamocortical networks depend critically on activation of low- and high-voltage-activated (LVA, HVA) Ca2+ currents. In order to test whether Ca2+ currents are modified during repetitive activation, acutely isolated thalamocortical relay neurons of rats, at postnatal days 12 (P12) to P20, were investigated using patch-clamp, Ca2+ imaging and Western blot techniques. High-voltage-activated, but not LVA Ca2+ currents were reduced significantly during 2 Hz stimulation. Ca2+ imaging experiments demonstrated a close correlation between the increase in intracellular Ca2+ levels and the decrease in HVA Ca2+ current amplitudes. Further examination of HVA Ca2+ currents revealed a 'U-shaped' inactivation curve and a time-dependent inactivation process that could be described by a two-exponential function. The 'U-shape' was significantly reduced, current amplitude was increased significantly and time-dependent inactivation revealed a one-exponential decline with Ba2+ as the charge carrier, following activation of the cAMP/PKA pathway, and following application of phosphatase inhibitors (ascomycin, calyculin A). Western blot analysis and the effect of ascomycin indicated an involvement of calcineurin in the inactivation process. Isolation of HVA Ca2+ current components by subtype-specific blockers revealed that changes in time-dependent inactivation, inactivation curve and current amplitude were carried mainly by L-type and N-type Ca2+ currents. Furthermore, Ca2+-dependent inactivation was operative during stimulation protocols mimicking tonic action potential firing. These data indicate a modulation of L- and N-type Ca2+ channels by phosphorylation, resulting jointly in an increased intracellular Ca2+ influx during activity of the ascending brainstem system, the latter occurring during states of wakefulness.

Brain death assessment using instant spectral analysis of heart rate variability.

Confirmation of brain death requires an urgent diagnosis to allow rapid vital organ removal for transplantation. Evaluation of forebrain functions is commonly performed through electroencephalogram. Nevertheless, there are, for the moment, no methods that allow for an instantaneous evaluation of brainstem functions. During acute brain injury, heart rate variability is an independent neurologic prognosis indicator resulting from a close relationship between brain stem and cardiac autonomic nervous system. This study aims to evaluate a new heart rate variability spectral analysis method, on a beat-to-beat basis, continuously over the time, during brain death. Prospective, nonrandomized, observational study. Intensive care unit. Ten patients (age range 25-64 yrs, mean age 41 yrs) with acute brain injury leading to brain death. No intervention beyond standard of care Heart rate, arterial blood pressure, heart rate variability in time and frequency domains method, which included calculation of the instant center frequency of spectrum. Brain death was associated with tachycardia (R-R interval 703 +/- 69 vs. 551 +/- 34 msec, p <.05), dramatic reduction of the global spectral power (44.919 +/- 31.511 vs. 3.204 +/- 1.469 msec(2), p <.05), and an abrupt shift of instant center frequency to a higher frequency range (0.17 +/- 0.01 vs. 0.26 +/- 0.03 Hz, p <.05). Such a method allows an instant, noninvasive determination of brainstem death based on a time and frequency domain analysis of heart rate variability.

Immediate-early Fos Protein Levels in Brainstem Neurons of Male and Female Gonadectomized Mice Subjected to Cold Exposure

The expression of the immediate early gene c-fos has been used extensively as a marker for neural activation in response to acute and chronic stressful stimuli in brain and spinal cord. The present study examined the expression of Fos protein in the brainstem nuclei of male and female gonadectomized mice in response to cold stress. Free-floating sections were processed immunohistochemically for Fos protein using standard avidin-biotin complex methods. The number of Fos-positive neurons in each nucleus was determined. Although the experiment was designed to look for gender differences, results were equivalent between females and males. After mice were exposed to a cold ambient temperature (4°C) for 2 h, elevated numbers of Fos-positive neurons were counted in the medullary gigantocellular reticular nucleus, medullary raphe nucleus, nucleus of the solitary tract and in locus coeruleus. However, no elevated expression was found in nucleus ambiguus, nor in neurons of the A1 group, nor the C2 or C3 group. Similar to rats, these results with mice reveal a widespread arousal system in the lower brainstem activated by cold stress in both genders. These findings in gonadectomized mice have set the stage for investigations following hormonal and genetic manipulations.

Relationship between correlation dimension and indices of linear analysis in both respiratory movement and electroencephalogram

Objective: We investigate the relationships between signals from the electroencephalogram (EEG) and those from respiratory movement using the correlation dimension (D2).Methods: Respiratory movement and EEG were recorded for 7.5h from 7 clinically healthy men. D2 was calculated by applying an algorithm slightly modified from that proposed by Grassberger and Procaccia (Phys Rev Lett 50 (1983) 346). Non-linearity in respiratory movement and EEG was tested by comparing D2 for the original data with that for surrogate data.Results: A statistically significant positive correlation between D2 of the EEG and D2 of the respiratory movement was observed for the original data, but not for the surrogate data.Conclusions: A reduced D2 of the EEG may be associated with an increased regularity of breathing in deep sleep (stage IV). Likewise, the increased D2 of respiratory movement during rapid eye movement may be associated with increased complexity of the signals. Whether there is a direct coordination between brain and lungs or whether brainstem systems, including that of the cholinergic system, affect both respiration and cortex requires further investigation.

The Relationships of Brain Stem Systems to Their Targets in the Spinal Cord of the Eel, Anguilla anguilla

We have investigated the detail with which supraspinal neurons innervate different regions in the spinal cord. Horseradish peroxidase was applied at different levels of the cord: (1) to the cut surface; (2) injected iontophoretically into one side; or (3) into one of the motoneuron pools innervating different muscle compartments. In all cases, labeled neurons were found throughout the brain distributed over nuclear groups identified in previous fish studies. Some cells from all but one of the nuclei have axons that extend over the whole length of the cord and about 50% of all neurons project to post-anal levels. No topographical distribution relating somal position and target location was found. Sixty seven percent of the neurons send axons to the ipsilateral side of the cord, although most nuclear groups provide a bilateral projection. Nucleus ruber projects entirely contralaterally. The descending and magnocellular octavolateral nuclei, and the descending nucleus of the trigeminal nerve project entirely ipsilaterally. Neurons that project to the spinal motoneuron pools innervating the myotomal red- or white-muscle are distributed throughout the same brain stem nuclei, but the cell bodies of those neurons innervating white-muscle motoneurons are larger. Nineteen pairs of cells were found to be consistently identifiable and all project to all levels of the cord; they were only labeled from injections made into the white-muscle motoneuron pool.

Origin of the Precerebellar System

The precerebellar system provides the principal input to the cerebellum and is essential for coordinated motor activity. Using a FLP recombinase–based fate mapping approach, we provide direct evidence in the mouse that this ventral brainstem system derives from dorsally located rhombic neuroepithelium. Moreover, by fate mapping at the resolution of a gene expression pattern, we have uncovered an unexpected subdivision within the precerebellar primordium: embryonic expression of Wnt1 appears to identify the class of precerebellar progenitors that will later project mossy fibers from the brainstem to the cerebellum, as opposed to the class of precerebellar neurons that project climbing fibers. Differential gene expression therefore appears to demarcate two populations within the precerebellar primordium, grouping progenitors by their future type of axonal projection and synaptic partner rather than by final topographical position.

Nonstationary time-series analysis applied to investigation of brainstem system dynamics.

Previous investigations of the dynamic organization of the lower brainstem and its relation to peripheral and other central nervous systems were predominantly performed by linear methods. These are based on time-averaging algorithms, which merely can be applied to stationary signal intervals. Thus, the current concept of the common brainstem system (CBS) in the reticular formation (RF) of the lower brainstem and basic types of its functional organization have been developed. Here, we present experiments where neuronal activities of the RF and the nucleus tractus solitarii (NTS, first relay station of baroreceptor afferents) were recorded together with related parameters of electroencephalogram (EEG), respiration, and cardiovascular system. The RF neurons are part of the CBS, which participates in regulation and coordination of cardiovascular, respiratory, and motor systems, and vigilance. The physiological time series, thus acquired, yield information about the internal dynamic coordination of the participating regulation processes. The major problem in evaluating these data is the nonlinearity and nonstationarity of the signals. We used a set of especially designed time resolving methods to evaluate nonlinear dynamic couplings in the interaction between CBS neurons and cardiovascular signals, respiration and the EEG, and between NTS neurons (influenced by baroreceptor afferents) and CBS neurons.

Phase transitions in the common brainstem and related systems investigated by nonstationary time series analysis

Neuronal activities of the reticular formation (RF) of the lower brainstem and the nucleus tractus solitarii (NTS, first relay station of baroreceptor afferents) were recorded together in the anesthized dog with related parameters of EEG, respiration and cardiovascular system. The RF neurons are part of the common brainstem system (CBS) which participates in regulation and coordination of cardiovascular, respiratory, somatomotor systems, and vigilance. Multiple time series of these physiological subsystems yield useful information about internal dynamic coordination of the organism. Essential problems are nonlinearity and instationarity of the signals, due to the dynamic complexity of the systems. Several time-resolving methods are presented to describe nonlinear dynamic couplings in the time course, particularly during phase transitions. The methods are applied to the recorded signals representing the complex couplings of the physiological subsystems. Phase transitions in these systems are detected by recurrence plots of the instationary signals. The pointwise transinformation and the pointwise conditional coupling divergence are measures of the mutual interaction of the subsystems in the state space. If the signals show marked rhythms, instantaneous frequencies and their shiftings are demonstrated by time frequency distributions, and instantaneous phase differences show couplings of oscillating subsystems. Transient signal components are reconstructed by wavelet packet time selective transient reconstruction. These methods are useful means for analyzing coupling characteristics of the complex physiological system, and detailed analyses of internal dynamic coordination of subsystems become possible. During phase transitions of the functional organization (a) the rhythms of the central neuronal activities and the peripheral systems are altered, (b) changes in the coupling between CBS neurons and cardiovascular signals, respiration and the EEG, and (c) between NTS neurons (influenced by baroreceptor afferents) and CBS neurons occur, and (d) the processing of baroreceptor input at the NTS neurons changes. The results of this complex analysis, which could not be done formerly in this manner, confirm and complete former investigations on the dynamic organization of the CBS with its changing relations to peripheral and other central nervous subsystems.

The neuropathology of schizophrenic diseases: historical aspects and present knowledge.

In the first half of the century, histological abnormalities in the cortex and thalamus of schizophrenics were described. These findings, however, remained controversial and finally were widely forgotten. More recently, a large number of structural imaging studies convincingly showed subtle structural changes such as ventricular enlargement, cortical sulcal enlargement, and smaller hippocampi in a considerable proportion of schizophrenic patients. Many studies reported minor tissue abnormalities in limbic structures. Since the limbic system is anatomically and functionally interposed between the neocortical association areas and phylogenetically old hypothalamic and brain stem systems, limbic dysfunction may lead to a dissociation between cognitive activities and basic emotional reactions, thus, explaining some aspects of the psychopathology of schizophrenia. Reduced cortical asymmetry, lack of gliosis, and other findings support the idea of a disorder of early brain development; however, a progressive component also might be inherent.

In Reply

Back to table of contents Previous article Next article LetterFull AccessIn ReplyBruno Baumann, M.D., Bruno BaumannSearch for more papers by this author, M.D., Department of Psychiatry, Otto-von-Guericke-University of Magdeburg, GermanyPublished Online:1 Nov 1999https://doi.org/10.1176/jnp.11.4.515-aAboutSectionsView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Dr. Lauterbach has made some encouraging comments on our report that patients with a history of unipolar or bipolar depression have a smaller external globus pallidus (GPe) than control subjects. He referenced additional literature on the significance of pallidal pathology in depressive states. We would like to respond by addressing issues for further research in this field.First, there is the question of whether diagnostic dichotomy is reflected by structural brain pathology. In our study we found no volume differences in the basal ganglia between subjects with bipolar and those with unipolar disorder. If this result is confirmed by studies of larger samples, then arguably the pathomorphology of depressive states is unrelated to diagnostic polarity. This finding could be of interest because the most recently reported data suggest that the brain structure in bipolar disorder differs regionally from that in unipolar depression.1–3 Thus, although neuroanatomic circuits might differ in bipolar and unipolar depression, some elements might be consistently present in both disorders and show similar changes. For instance, limbic-associated basal ganglia might be common elements in the neural networks underlying depression in bipolar and in unipolar illness.As emphasized by Dr. Lauterbach, the dorsal and ventral parts of the GPe mediate different effects on thalamic-frontocortical circuits and should be given more attention in future studies on the morphology of depression. Also, structural data are needed on the involvement in primary and secondary depressive disorders of the mediodorsal thalamus and specific frontocortical regions such as the dorsolateral, orbitofrontal, and medial frontal cortex, which are considered in neuroanatomic models of depressive behavior.4,5 Such results would allow for better ascertainment of the frontal-subcortical circuits implicated in the pathomorphology of depression. Dr. Lauterbach's proposal, that structural changes in the GPe may result in depressive states irrespective of etiology, could be extended to wider parts of these circuits. If evidence of wider involvement emerges, then factors affecting these regions in the developing or the adult brain should be taken into account when planning future strategies for the treatment and prevention of depressive disorder.References1 Altshuler LL, Bartzokis G, Grieder T, et al: Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry 1998; 55:663–664Medline, Google Scholar2 Strakowski SM, DelBello MP, Sax KW, et al: Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry 1999; 56:254–260Crossref, Medline, Google Scholar3 Baumann B, Danos P, Krell D, et al: Unipolar-bipolar dichotomy of mood disorders is supported by noradrenergic brainstem system morphology. J Affect Disord 1999; 54:217–224Crossref, Medline, Google Scholar4 Masterman DL, Cummings JL: Frontal-subcortical circuits: the anatomic basis of executive, social and motivated behaviors. J Psychopharmacol 1997; 11:107–114Crossref, Medline, Google Scholar5 Soares JC, Mann JJ: The anatomy of mood disorders: review of structural neuroimaging studies. Biol Psychiatry 1997; 41:86–106Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 11Issue 4 November 1999Pages 515-a-516 Metrics History Published online 1 November 1999 Published in print 1 November 1999

Unipolar–bipolar dichotomy of mood disorders is supported by noradrenergic brainstem system morphology

Background: The biological basis of unipolar-bipolar dichotomy of mood disorders was investigated in this postmortem study by morphological comparison of the locus coeruleus (LC) as the main source of noradrenergic transmission in the brain. Methods: Numbers and the rostro-caudal as well as ventro-dorsal distribution of neuromelanin-containing neurones in the LC were determined in brainstem of 12 patients with bipolar disorder ( n=6) or major depression ( n=6), and 12 normal comparison subjects. Results: Bipolar patients had significantly more neurones on both sides of the LC as a whole than patients with major depression. Topographical analysis revealed that this difference was restricted to the rostral two thirds and the dorsal part of the LC, in which bipolar patients showed at least a trend to higher neurone numbers as compared to unipolar patients or to controls. Limitations: Small case numbers. Conclusions: Results suggest differences of innervation arising from the LC of bipolar patients as compared to patients with major depression. These first data of brainstem transmitter system morphology in unipolar and bipolar disorder are in line with neuroanatomical studies of other brain regions indicating a biological basis of the unipolar-bipolar dichotomy of mood disorders.

Common slow modulation of respiration, arterial blood pressure and cortical activity during sleep onset while napping.

Using healthy subjects, concomitant 30- to 60-s modulations of respiration, arterial blood pressure and EEG activity were found in 21 experiments about napping. Although mean arterial pressure (MAP) modulations above and below 1/30 Hz increased, in respiratory amplitude (RA) only the lower frequency components augmented significantly. This slow modulation of RA was found to be asymmetrical in time, the duration of RA decreasing parts in the modulation waves being 42% longer than the duration of RA increasing parts. The concomitance of the slow modulations in the different organ systems is accounted for by the influence of the common brainstem system (CBS), which regulates and integrates respiratory, cardiovascular and somatomotor systems and the adjustment of central nervous activity (vigilance). The described common, slow modulations outline the importance of dampening influences during sleep onset. They may provide an important tool for the investigation of the regulatory systems during sleep onset, as well as for investigations about sleep apnoea syndrome and Cheyne-Stokes breathing.

Chapter 37 Animal Models of Motor Systems: Cautionary Tales from Studies of Head Movement

Studies of motor systems have always depended in large measure on the use of cats as experimental animals, and those of the head-movement system are no different. To understand the coupling from forelimb to neck through the shoulder, it is necessary to know the position of the feline clavicle and scapula with respect to the joints of the neck. These positions and centers of rotation determine the moment-generating capacity of several key muscles and the transmission of forces through the bones and ligaments of the joints. In cats, much of the research done to date has been concerned with the coordination of head and eye movements. The work suggests the presence of at least two separate brainstem systems controlling the vertical and horizontal components of combined head and eye movements in such diverse species as cats, owls, and man. It also suggests substantial task-related specificity among the neck muscles. Vertical movements appear to be produced by recruiting extensor muscles containing high proportions of slow fibers. Particularly important are the biventer cervicis and occipitoscapularis, which are active tonically when the head is raised or held stationary in most postures, and which even show activity as the head is lowered in a controlled way from a high-held to a low-held position. Muscles associated with horizontal movements, in contrast, tend to have high proportions of fast fibers.

Pharmacologic Treatment of Migraine

The vascular theory of migraine proposed by Wolff, attributing migrainous symptoms to paroxysmal constriction and dilation of the cranial vasculature, held sway for over four decades and even now remains embraced by many clinicians and the lay public. Recent investigations, however, suggest that this proposed mechanism is untenable; although changes in blood vessel caliber and blood flow do occur in some patients during some attacks, they are not required for the production of migrainous symptoms and appear to be largely epiphenomena, occurring subsequent (and consequent) to another primary process. Evidence is mounting that migraine may result from a pathologic alteration of neurotransmission within the brain stem and trigeminovascular system, and one of the neurotransmitters primarily involved is serotonin. This has led to an explosion of interest in therapeutic agents which influence serotoninergic receptors, and the astounding success enjoyed by the first of these agents to be utilized clinically (sumatriptan and dihydroergotamine) and their offspring suggests that our understanding of this common and vexing problem will increase and be paralleled by the identification of yet more specific and effective treatment intervention.

The central questions in pain perception may be peripheral

Pain and its control are still a daunting problem. Although drugs such as morphine have been around since ancient times and recent years have seen the introduction of a number of additional painkillers, many gaps remain in our ability to control the suffering of pain. Pain is an emotional response that is triggered by nociceptive inputs from the periphery that are transmitted centrally to the spinal cord and then ascend through the paleospinothalamic tracts to limbic structures. The complexity of pain perception reflects the presence of both nociceptive and antinociceptive systems that modulate nociceptive input at many levels of the neuraxis (1). Descending brainstem systems influence nociceptive stimuli spinally while other systems modulate nociceptive input supraspinally. The opioid peptides and their receptors comprise the most efficacious antinociceptive systems, effectively relieving the suffering component of pain without interfering with basic sensation (2). They comprise a complex collection of many discrete, but interacting, receptor systems. All the various classes of opioid receptors and the numerous opioid peptides have been implicated in pain modulation.