Visceral nociception: peripheral and central aspects of visceral nociceptive systems

Discomfort and pain are the sensations most commonly evoked from viscera. Most nociceptive signals that originate from visceral organs reach the central nervous system (c.n.s.) via afferent fibres in sympathetic nerves, whereas parasympathetic nerves contain mainly those visceral afferent fibres concerned with the non-sensory aspects of visceral afferent function. Noxious stimulation of viscera activates a variety of specific and non-specific receptors, the vast majority of which are connected to unmyelinated afferent fibres. Studies on the mechanisms of visceral sensation can thus provide information on the more general functions of unmyelinated afferent fibres. Specific visceral nociceptors have been found in the heart, lungs, testes and biliary system, whereas noxious stimulation of the gastro-intestinal tract appears to be detected mainly by non-specific visceral receptors that use an intensity-encoding mechanism. Visceral nociceptive messages are conveyed to the spinal cord by relatively few visceral afferent fibres which activate many central neurons by extensive functional divergence through polysynaptic pathways. Impulses in visceral afferent fibres excite spinal cord neurons also driven by somatic inputs from the corresponding dermatome (viscero-somatic neurons). Noxious intensities of visceral stimulation are needed to activate viscero-somatic neurons, most of which can also be excited by noxious stimulation of their somatic receptive fields. The visceral input to some viscero-somatic neurons in the spinal cord can be mediated via long supraspinal loops. Pathways of projection of viscero-somatic neurons include the spino-reticular and spino-thalamic tracts. All these findings give experimental support to the 'convergence-projection' theory of referred visceral pain. Visceral pain is the consequence of the diffuse activation of somato-sensory nociceptive systems in a manner that prevents accurate spatial discrimination or localization of the stimuli. Noxious stimulation of visceral receptors triggers general reactions of alertness and arousal and evokes unpleasant and poorly localized sensory experiences. This type of response may be a feature of sensory systems dominated by unmyelinated afferent inputs.     

Laminar distribution of the cells of origin of the spinocerebral pathways involved in nociceptive transmission and pain modulation in the rat

The laminar distribution of spinomesencephalic, spinothalamic, and spinotelencephalic tract neurons, and the pattern of axonal collateralization in these spinocerebral pathways were studied in the rat by means of retrograde double-labelling of the cells with fluorescent dyes Fluoro-Gold and Primuline O. We found that sources of spinocerebral pathways to the analgesic brainstem centers, as well to thenucl. accumbens and septal nuclei, were mixed together in the marginal zone (lamina I, by Rexed), in the deep dorsal horn (laminae IV–VI), in the area around the central canal (lamina X), and within the lateral spinal nucleus. At the same time, all the above pathways retain their own specific projection fields. Thus, these spinocerebral projections could be characterized as extensive, but not diffuse. We propose that the main effect of activation of the direct spinal inputs to the limbic system is an increase in nociceptive sensitivity, but not a suppression of nocicptive transmission at the the spinal cord level.Neirofiziologiya/Neurophysiology, Vol. 28, No. 2/3, pp. 141–150, March–June, 1996.     

Spinal processing: anatomy and physiology of spinal nociceptive mechanisms

The processing of nociceptive input that occurs at the spinal level represents the first stage of effective control over its access to higher regions of the central nervous system. Recent developments in both the anatomy and physiology of nociceptive processing pathways at this level are beginning to yield an integrated understanding of structure and function. Most small afferent axons terminate in the more superficial laminae of dorsal horn, but technical difficulties have, until recently, prevented analysis of the functional properties of identified small fibres. A direct input of nociceptive afferents on to particular dorsal horn neurons is difficult to establish in view of the slow impulse conduction in these fibres and the small size of target neurons in the substantia gelatinosa. The small cells themselves are being analysed for relations between structure and function, using physiological, intracellular staining and immunocytochemical techniques to characterize their properties. They appear to be a highly heterogeneous population with many sub-classes, whether typed according to the transmitter they contain, e.g. enkephalin, to their physiological responses: whether excitatory or inhibitory to nociceptive and other inputs, or to both. The multireceptive neurons that project out of the dorsal horn toward supraspinal regions are, in general, located in deeper laminae and are likely to receive nociceptive information through polysynaptic pathways. The nocireceptive neurons in lamina I, which receive exclusively nociceptive inputs from myelinated and non-myelinated afferents project, at least in part, to thalamic and brain stem regions. Polysynaptic nociceptive pathways in dorsal horn may be subject to different controls from neurons in laminae I and II. Tonic descending inhibition is operative on the former and it is becoming clearly established that descending systems such as those containing noradrenaline, can regulate the access of nociceptive information to higher levels. The mechanisms of such descending controls and the importance of their interaction with segmental control systems, such as those involving the dynorphin opioids, are just beginning to be understood. Many somatosensory neurons in dorsal horn, both the large cells, some of which project supraspinally, and the small cells of superficial laminae, receive convergent nociceptive and non-nociceptive inputs. Although solely nociresponsive neurons are clearly likely to fill a role in the processing and signalling of pain in the conscious central nervous system, the way in which such useful specificity could be conveyed by multireceptive neurons is difficult to appreciate.(ABSTRACT TRUNCATED AT 400 WORDS)     

Medial, intralaminar, and lateral terminations of lumbar spinothalamic tract neurons: a fluorescent double-label study

A dorsolateral spinothalamic tract (DSTT), consisting primarily of lamina I neurons, was confirmed in the cat lumbar spinal cord by the use of thalamic injections of fluorescent dyes combined with selective thoracic spinal cord lesions. In addition, collateralization of spinothalamic tract (STT) terminations to medial, lateral, and intralaminar thalamic regions was investigated by injections of two different fluorescent dyes into pairs of these regions. The results of this study indicate that less than 15% of cat lumbar STT neurons collateralize to more than one of the thalamic regions evaluated. Lumbar lamina I cells project to the lateral and to the medial thalamus (13% collateralize to these two regions) and have only a scant projection to the intralaminar thalamus. Lumbar laminae IV-VI STT cells are very few in cat and demonstrate almost no collateralization to multiple thalamic areas. Neurons of laminae VII-X project equally to the three thalamic regions evaluated, and approximately 10-14% of cells from this laminar group collateralize to any two of the thalamic sites evaluated.     

Anatomy and physiology of a nociceptive modulatory system

Although efferent control of sensory transmission is a well-established concept, a specific network for nociceptive modulation has only recently been discovered. This network includes interconnected components at midbrain, medullary and spinal levels. At the midbrain level, electrical stimulation of the periaqueductal grey (p.a.g.) inhibits spinal neurons that respond to noxious stimuli as well as nociceptor-induced reflexes and escape behaviour in a variety of species. Midbrain stimulation also produces analgesia in patients with clinically significant pain. The rostral ventral medulla (r.v.m.) has similar behavioural and physiological effects and mediates midbrain antinociceptive actions at the level of the spinal cord. Endorphins are present at all levels of this nociceptive modulating network. Opiate microinjections at p.a.g., r.v.m. or spinal levels produce analgesia, presumably by mimicking the actions of the endorphins. The nociceptive modulatory system is diffusely organized, highly interconnected and appears to act as a unit whether activated by opiates or electrical stimulation. There are two classes of r.v.m. neurons the activity of which is correlated with the occurrence of reflexes induced by noxious stimulation. One class (the on-cell) accelerates, the other class (the off-cell) pauses just before tail flick. Both classes project to the spinal cord and are excited by electrical stimulation of the midbrain. However, when morphine is injected either systemically or into the p.a.g., the off-cell is excited and the on-cell stops firing. The off-cell is probably the r.v.m. output cell that inhibits nociceptive transmission at the level of the spinal cord. The function of the on-cell is not clear. The nociceptive modulatory system can be activated by a variety of stressful environmental factors, which are often, but not necessarily, noxious. The idea that the system acts as a simple negative feedback circuit is not consistent with its known properties.     

Cellular distribution and bioactivity of the key steroidogenic enzyme,cytochrome P450side chain cleavage,in sensory neural pathways

Neurosteroids are steroids produced within the nervous system. Based on behavioural responses evoked in animals by synthetic steroid injections, several studies suggested neurosteroid involvement in important neurophysiological processes. These observations should be correlated only to neuroactive effects of the injected steroids. Neurosteroids mostly control the CNS activity through allosteric modulation of neurotransmitter receptors within concentration ranges used by neurotransmitters themselves. Therefore, neurosteroid production within pathways controlling a neurophysiological process is necessary to consider neurosteroid involvement in that process. Because of the increasing speculation about pain modulation by neurosteroids based on pharmacological observations, we decided to clarify the situation by investigating neurosteroidogenesis occurrence in sensory pathways, particularly in nociceptive structures. We studied the presence and activity of cytochrome P450side chain cleavage (P450scc) in rat pain pathways. P450scc-immunoreactive cells were localized in dorsal root ganglia (DRG), spinal cord (SC) dorsal horn, nociceptive supraspinal nuclei (SSN) and somatosensory cortex. Incubation of DRG, SSN or SC tissue homogenates with [3H]cholesterol yielded the formation of radioactive metabolites including [3H]pregnenolone of which the synthesis was reduced in presence of aminogluthetimide, a P450scc inhibitor. These first neuroanatomical and neurochemical results demonstrate the occurrence of neurosteroidogenesis in nociceptive pathways and strongly suggest that neurosteroids may control pain mechanisms.     

Objective assessment of clonidine analgesia in man and influence of naloxone

Experimental data indicate that clonidine can induce marked analgesia. We characterized this effect in healthy volunteers and investigated possible links with the opioid peptide system by means of naloxone antagonism. According to a cross-over, double-blind, placebo-controlled design, 10 subjects received oral and i.v. placebo or clonidine (0.2 mg p.o.) or clonidine and naloxone (2.8 mg i.v. in 5 h). Analgesia was assessed by measurement of the subjective pain threshold (visual analog scale) and the objective nociceptive flexion reflex (R III) threshold after transcutaneous electrical stimulations. A correlation was observed between subjective and objective thresholds (r: 0.78). Oral clonidine alone or with naloxone increased subjective and objective pain thresholds for at least 4 hours (p less than 0.01, ANOVA). Naloxone tended to reinforce clonidine analgesia. Only moderate and well tolerated side-effects were observed.     

Endothelin-1-induced nociception

Intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of morphine to mice antagonized the abdominal constriction induced by an i.p. injection of endothelin-1 (ET-1; 0.1 mg/kg). The ED50 values (95% confidence intervals) were 39.3 (16.5-80.2) ng and 1.5 (0.8-4.9) ng, respectively. The antagonism of ET-1-induced abdominal constriction by morphine was blocked by naloxone (1.0 mg/kg, s.c.) or by 24 h pretreatment with beta-funaltrexamine (beta-FNA; 8.84 micrograms, i.c.v.). These results demonstrate for the first time that the stimulus resulting from an i.p. injection of ET-1 is transmitted via ascending (pain) pathways that are subject to attenuation by opioid (mu) receptor activation. Hence, ET-1-induced abdominal constriction is a new pain model which, given the other pharmacology of ET-1, might represent a unique model with potential specific utility for anginal or other visceral pain.     

Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy

Long-term potentiation (LTP) in nociceptive spinal pathways shares several features with hyperalgesia and has been proposed to be a cellular mechanism of pain amplification in acute and chronic pain states. Spinal LTP is typically induced by noxious input and has therefore been hypothesized to contribute to acute postoperative pain and to forms of chronic pain that develop from an initial painful event, peripheral inflammation or neuropathy. Under this assumption, preventing LTP induction may help to prevent the development of exaggerated postoperative pain and reversing established LTP may help to treat patients who have an LTP component to their chronic pain. Spinal LTP is also induced by abrupt opioid withdrawal, making it a possible mechanism of some forms of opioid-induced hyperalgesia. Here, we give an overview of targets for preventing LTP induction and modifying established LTP as identified in animal studies. We discuss which of the various symptoms of human experimental and clinical pain may be manifestations of spinal LTP, review the pharmacology of these possible human LTP manifestations and compare it to the pharmacology of spinal LTP in rodents.     

Network dynamics in nociceptive pathways assessed by the neuronal avalanche model

ABSTRACT: BACKGROUND: Traditional electroencephalography provides a critical assessment of pain responses. The perception of pain, however, may involve a series of signal transmission pathways in higher cortical function. Recent studies have shown that a mathematical method, the neuronal avalanche model, may be applied to evaluate higher-order network dynamics. The neuronal avalanche is a cascade of neuronal activity, the size distribution of which can be approximated by a power law relationship manifested by the slope of a straight line (i.e., the alpha value). We investigated whether the neuronal avalanche could be a useful index for nociceptive assessment. FINDINGS: Neuronal activities were recorded with 4 X 8 multichannel electrode arrays in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC). Under light anesthesia, peripheral pinch stimulation increased the slope of the alpha value in both the ACC and S1, whereas brush stimulation increased the alpha value only in the S1. The increase in alpha values was blocked in both regions under deep anesthesia. The increase in alpha values in the ACC induced by peripheral pinch stimulation was blocked by medial thalamic lesion, but the increase in alpha values in the S1 induced by brush and pinch stimulation was not affected. CONCLUSIONS: The neuronal avalanche model shows a critical state in the cortical network for noxious-related signal processing. The alpha value may provide an index of brain network activity that distinguishes the responses to somatic stimuli from the control state. These network dynamics may be valuable for the evaluation of acute nociceptive processes and may be applied to chronic pathological pain conditions.     

Response histogram shapes and tuning curves: The predicted responses of several cortical cell types to drifting gratings stimuli

The responses to visual stimuli of simple cortical cells show linear spatial summation within and between their receptive field subunits. Complex cortical cells do not show this linearity. We analyzed the simulated responses to drifting sinusoidal grating stimuli of simple and of several types of complex cells. The complex cells, whose responses are seen to be half-wave rectified before pooling, have receptive fields consisting of two or more DOG (difference-of-Gaussians) shaped subunits. In both cases of stimulation by contrast-reversal gratings or drifting gratings, the cells' response as a function of spatial frequency is affected by the subunit distances 2 and the stimulation frequency . Furthermore, an increased number of subunits (a larger receptive field) yields a narrower peak tuning curve with decreased modulation depth for many of the spatial frequencies. The average and the peak response tuning curves are compared for the different receptive field types.     

Antinociceptive effect of spinally injected L-NAME on the acute nociceptive response induced by low concentrations of formalin

The formalin test has been proposed as an animal model of pain produced by tissue injury. Although biphasic nociceptive responses to formalin injection have been well documented, low concentrations (0.125 and 0.5%) of formalin injected into the mouse hindpaw produced only the phasic (acute) paw-licking response, lasting the first 5 min after the formalin injection. To explore the involvement of nitric oxide (NO) in the spinal cord and peripheral system during the acute phase of the formalin test, we examined the effect of intrathecal (i.t.) or intraplantar (i.pl.) injection of L-N(G)-nitro arginine methyl ester (L-NAME), a NO synthase inhibitor in mice. Pretreatment with L-NAME (160 nmol), injected i.t., resulted in a significant inhibition of the paw-licking response induced by 0.125 and 0.5% of formalin. L-Arginine (600 mg/kg, i.p.) but not D-arginine (600 mg/kg, i.p.) reversed the antinociceptive effect of L-NAME on the acute nociceptive response induced by low concentrations of formalin. The i.pl. injection of L-NAME (160 nmol) produced a significant decrease of the late (tonic) phase response evoked by 2.0% formalin without affecting the early (acute) phase response. Similar results have been reported in the case of i.t. injected L-NAME as assayed by the 2.0% formalin test. L-NAME (160 nmol), injected into the plantar paw, gave no significant effect on the acute nociceptive response induced by a low concentration of formalin (0.125%). These results suggest that NO in the spinal cord may be involved in not only the late phase response of the formalin (2.0%)-induced paw-licking, but also at least the acute phase response induced by low concentrations (0.125 and 0.5%) of formalin, while peripheral NO has little effect on the early (acute) phase nociceptive response evoked by formalin (0.125--2.0%) injection.     

Modeling convergent ON and OFF pathways in the early visual system

For understanding the computation and function of single neurons in sensory systems, one needs to investigate how sensory stimuli are related to a neuron’s response and which biological mechanisms underlie this relationship. Mathematical models of the stimulus–response relationship have proved very useful in approaching these issues in a systematic, quantitative way. A starting point for many such analyses has been provided by phenomenological “linear–nonlinear” (LN) models, which comprise a linear filter followed by a static nonlinear transformation. The linear filter is often associated with the neuron’s receptive field. However, the structure of the receptive field is generally a result of inputs from many presynaptic neurons, which may form parallel signal processing pathways. In the retina, for example, certain ganglion cells receive excitatory inputs from ON-type as well as OFF-type bipolar cells. Recent experiments have shown that the convergence of these pathways leads to intriguing response characteristics that cannot be captured by a single linear filter. One approach to adjust the LN model to the biological circuit structure is to use multiple parallel filters that capture ON and OFF bipolar inputs. Here, we review these new developments in modeling neuronal responses in the early visual system and provide details about one particular technique for obtaining the required sets of parallel filters from experimental data.     

Supraspinal injection of Substance P attenuates allodynia and hyperalgesia in a rat model of inflammatory pain

The neuropeptide Substance P (SP), that has a high affinity for the neurokinin 1 (NK1) receptor, is involved in modulation of pain transmission. Although SP is thought to have excitatory actions and promote nociception in the spinal cord, the peptide induces analgesia at the supraspinal level. The aim of this study was to evaluate the role of supraspinal SP and the NK1 receptor in inflammatory pain induced by injection of carrageenan in the hind paw of the rat. There are two nociceptive behavioral responses associated with this pain state: mechanical allodynia and heat hyperalgesia. Because the NK1 receptor colocalizes with the MOP receptor in supraspinal sites involved in pain modulation, we also decided to study the possible involvement of the opioid system on SP-induced analgesia. We found that treatment with SP, at doses of 3.5, 5 and 7 μg/5 μl/rat i.c.v., clearly showed inhibition of allodynia and hyperalgesia. Pretreatment with the selective NK1 antagonist L-733,060 (10mg/kg i.p.) blocked the SP-induced analgesia, suggesting the involvement of the NK1 receptor. This SP-induced analgesia was significantly reduced by administration of the opioid antagonist naloxone (3mg/kg s.c.). This reduction occurred when SP was administered either before or after the carrageenan injection. These results suggest a significant antinociceptive role for SP and the NK1 receptor in inflammatory pain at the supraspinal level, possibly through the release of endogenous opioids.     

Immature spinal cord neurons are dynamic regulators of adult nociceptive sensitivity

Chronic pain is a debilitating condition with unknown mechanism. Nociceptive sensitivity may be regulated by genetic factors, some of which have been separately linked to neuronal progenitor cells and neuronal differentiation. This suggests that genetic factors that interfere with neuronal differentiation may contribute to a chronic increase in nociceptive sensitivity, by extending the immature, hyperexcitable stage of spinal cord neurons. Although adult rodent spinal cord neurogenesis was previously demonstrated, the fate of these progenitor cells is unknown. Here, we show that peripheral nerve injury in adult rats induces extensive spinal cord neurogenesis and a long‐term increase in the number of spinal cord laminae I–II neurons ipsilateral to injury. The production and maturation of these new neurons correlates with the time course and modulation of nociceptive behaviour, and transiently mimics the cellular and behavioural conditions present in genetically modified animal models of chronic pain. This suggests that the number of immature neurons present at any time in the spinal cord dorsal horns contributes to the regulation of nociceptive sensitivity. The continuous turnover of these neurons, which can fluctuate between normal and injured states, is a dynamic regulator of nociceptive sensitivity. In support of this hypothesis, we find that promoters of neuronal differentiation inhibit, while promoters of neurogenesis increase long‐term nociception. TrkB agonists, well‐known promoters of nociception in the short‐term, significantly inhibit long‐term nociception by promoting the differentiation of newly produced immature neurons. These findings suggest that promoters of neuronal differentiation may be used to alleviate chronic pain.     

去甲肾上腺素在脊髓背角的镇痛机制

疹髓背角浅层是传递和调制外周伤害性信息的关键部位。起源于脑干的去甲肾上腺素（NA）能纤维终止脊髓背角,它们释放的NA具有抑制初级传入末梢释放谷氨酸和P物质、增加Ⅱ层（胶状质）抑制性神经活性物质释放的作用。此外,形态学研究提示NA可能直接抑制Ⅰ/Ⅲ层向丘脑传递伤害性信息的投射神经元。NA可能通过以上途径,实现对外周伤害性信息传递的调制而发挥镇痛作用。     

Additive effects of PDGF receptor beta signaling pathways in vascular smooth muscle cell development

The platelet-derived growth factor beta receptor (PDGFRbeta) is known to activate many molecules involved in signal transduction and has been a paradigm for receptor tyrosine kinase signaling for many years. We have sought to determine the role of individual signaling components downstream of this receptor in vivo by analyzing an allelic series of tyrosine-phenylalanine mutations that prevent binding of specific signal transduction components. Here we show that the incidence of vascular smooth muscle cells/pericytes (v/p), a PDGFRbeta-dependent cell type, can be correlated to the amount of receptor expressed and the number of activated signal transduction pathways. A decrease in either receptor expression levels or disruption of multiple downstream signaling pathways lead to a significant reduction in v/p. Conversely, loss of RasGAP binding leads to an increase in this same cell population, implicating a potential role for this effector in attenuating the PDGFRbeta signal. The combined in vivo and biochemical data suggest that the summation of pathways associated with the PDGFRbeta signal transduction determines the expansion of developing v/p cells.     

Stimulus size selectivity and receptive field organization of ectostriatal neurons in the pigeon

The avian ectostriatum is the telencephalic recipient zone of the tectofugal pathway, which may be homologous to the colliculo-pulvinar-cortical pathway in mammals. The present paper studies the visual response properties and receptive field organization of ectostriatal cells in pigeons with extracellular recording and computer mapping techniques. The results indicate that 90% of ectostriatal cells prefer forward, downward and upward motion of visual stimuli at velocities in the range of 16-128 degrees s(-1). They respond optimally to small stimuli (1-4 degrees visual angle), mostly preferring a target of 2 degrees. Most cells (78.8%) have one excitatory receptive field that usually possesses one or two hotspots, some cells (13.5%) have two excitatory receptive fields each having one or two hotspots, and a few cells (7.7%) have one excitatory receptive field with an unresponsive region in the center. An inhibitory receptive field is not found surrounding the excitatory receptive field in the ectostriatal cells examined. These response properties and receptive field organization may reflect the possible roles of the ectostriatum in stimulus discrimination and visual cognition.     

Enhanced antinociception by intracerebroventricularly and intrathecally-administered orexin A and B (hypocretin-1 and -2) in mice

Orexins are neuropeptides located exclusively in neurons of the lateral hypothalamic area, which send projections to most monoaminergic nuclei, such as noradrenergic locus coeruleus, dopaminergic ventral tegmental areas, and histaminergic tuberomammillary nuclei. The present work was carried out to examine the role of orexins in nociception in mice. C57BL/6 mice were administered with orexin A and B intracerebroventricularly (i.c.v.), intrathecally (i.t.) and subcutaneously (s.c.) to reveal the sites of action of these peptides and to examine the pain thresholds using four kinds of nociceptive tasks. Orexins showed antinociceptive effects in all four types of assays for thermal (hot-plate, tail-flick, paw-withdrawal), mechanical (tail-pressure), chemical (formalin, capsaicin and abdominal stretch) nociceptions and nociceptin-induced behavioral responses, when administered i.c.v. or i.t., whereas the s.c. administration was ineffective. The antinociceptive effects of orexin A were more remarkable than those of orexin B. The i.c.v. administration of orexin A was as effective as, or more potent than the i.t. administration. The effects of orexin A were completely blocked by adenosine type 1 receptor antagonists, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and theophylline, but not by naloxone, suggesting a possible involvement of the adenosine-containing neurons and/or the adenosine pathway in these orexin actions. The i.c.v. administration of nociceptin had no significant effects on orexin expression in the brain and spinal cord. The present findings suggest that orexins have an antinociceptive role in at least four different types of pains, probably acting on both the brain and spinal cord.