Nociceptive nerve fibers in the sacroiliac joint in humans.

BACKGROUND AND OBJECTIVES: A positive response to sacroiliac joint intra-articular infiltration with local anesthetics is used to confirm sacroiliac joint pain. However, current anatomical and histological knowledge concerning the anatomy of pain perception within the sacroiliac joint intra- and peri-articular structures is insufficient to explain the efficacy of this infiltration, because of the use of unspecific histochemical visualization techniques. METHODS: In this study, immunohistochemistry for calcitonin gene-related peptide (CGRP) and substance P was used to trace nociceptive fibers and receptors in the anterior and interosseous sacroiliac ligaments obtained from 5 human cadavers without history of sacroiliac joint pain. RESULTS: Microscopic analysis of stained slides showed presence of CGRP and substance P immunoreactive fibers. Thick, wavy, formed bundles were observed in dense and loose connective tissue, whereas single, beaded nerve fibers, occasionally ramified, were observed more frequently in the dense connective tissue and next to blood vessels. Based on their morphologic features, these immunoreactive structures were classified as receptors type IV. Additionally, receptors type II were found in anterior and interosseous ligaments, which contained CGRP or substance P immunoreactive free nerve endings. CONCLUSIONS: We conclude that the presence of CGRP and substance P immunoreactive fibers in the normal anterior capsular ligament and interosseous ligament provides a morphological and physiological base for pain signals originating from these ligaments. Therefore, diagnostic infiltration techniques for sacroiliac joint pain should consider extra- as well as intra-articular approaches.

Biochemical aspects of chronic pain and its relationship to treatment.

This review presents an overview of the neurotransmitters and neuromodulators involved in acute and chronic pain. Although there is little evidence that the neuronal pathways differ in the two types of pain, it is clear that different transmitters or receptor types are involved in hyperalgesia and chronic pain. While most attention has been focussed on spinal processes, it is apparent that some types of chronic pain have both a peripheral and a supraspinal component. The presently available drugs are probably adequate for acute pain, but the treatment of chronic pain may need to be tailored to the individual patient.

Primary afferent axons in the tract of Lissauer in the monkey.

The main thrust of the present study was to determine the numbers of primary afferent fibers in the tract of Lissauer in the monkey. The findings are that approximately 40% of the axons in the tract of Lissauer are primary afferent axons from a single segment, and approximately another 40% are primary afferents from segments cranial and caudal to the segment under consideration. Presumably, the remaining 20% are propriospinal axons. There is relatively little difference in the proportions of primary afferents in medial as opposed to lateral parts of the tract, and in this respect the monkey differs somewhat from the rat and cat. Thus in the monkey the tract of Lissauer should probably be regarded as a primary afferent pathway with the propriospinal forming a distinct but relatively minor component of the tract.

Distribution and morphology of nociceptive cells in the CNS of three species of leeches.

The present study describes the segmental variation in the distribution and morphology of nociceptive neurons (N cells) in the central nervous system of the leech. N cells of midbody ganglia can be segregated into lateral and medial types. We show that monoclonal antibodies specific for N cells can distinguish between the two populations. The monoclonal antibodies were used to map the complete distribution of the cells along the nervous cord. There are two pairs of the medial and lateral nociceptive neurons in the midbody ganglia, one pair of the medial type in the sex ganglia (5 and 6), and a pair of the lateral type in ganglia 20 and 21. The caudal brain is without nociceptive neurons. This distribution was confirmed by electrophysiological means. The morphology of N cells in different parts of the nervous system was investigated by intracellular horseradish peroxidase (HRP) injections. In the terminal segmental ganglia the N cells showed extensive arborizations in the head and tail brains and, contrary to N cells in the midbody ganglia, their arborizations spanned more than three segments. N cells are absent in the tail brain, but the N cells of ganglia 20 and 21 were shown to innervate the entire caudal region. The basic morphology of all N-cell homologues was found to be very similar for three leech species. In the sex ganglia the pair of N-cell homologues were examined in Haemopis, Hirudo, and Macrobdella. The results showed a progressive modification in the three species of the cell's morphology, peripheral projections, and physiological responses, possibly correlated with the evolution and complexity of the sexual organs. HRP injections and monoclonal antibody staining revealed that a common feature of N-cell homologues is the presence of processes that tightly surround the cell soma of other cells. This suggests that N cells may have other functional properties in addition to being primary sensory neurons.

GABA-immunoreactive neurons and terminals in the lateral cervical nucleus of the cynomolgus monkey.

An antiserum against the inhibitory transmitter substance gamma-aminobutyric acid (GABA) was used to investigate the distribution of GABAergic nerve terminals and cell bodies in the lateral cervical nucleus (LCN) of the cynomolgus monkey. Light microscopic immunohistochemistry demonstrated GABA-immunoreactive puncta, suggestive of nerve terminals, scattered throughout the LCN. The terminal-like profiles are often present along the somata of unlabeled neurons, but most are located in the neuropil. GABA-immunoreactive neurons are present in the LCN, but constitute a very small number of the LCN neurons. Electron microscopy showed that the GABA-positive neurons are small with a relatively large nucleus. They are contacted by few somatic boutons. Numerous GABA-immunoreactive terminals containing densely packed round to oval synaptic vesicles were also found. Most GABA-positive terminals make synaptic contact with dendrites, but synapses with cell bodies are also present. Synaptic contacts between labeled and unlabeled terminals were not observed. Some GABA-positive terminals make contact with GABA-positive neurons. The present findings suggest that GABA is a major inhibitory transmitter substance in the LCN of the monkey. However, in comparison with other somatosensory relay nuclei, there are few GABA-immunoreactive neurons in the LCN. This may imply that the GABA-positive neurons branch extensively in the LCN or that an extrinsic source of GABAergic input exists.

The morphology of dorsal column postsynaptic spinomedullary neurons in the cat.

Dorsal column postsynaptic ( DCPS ) spinomedullary neurons from the cat's lumbosacral enlargement were identified by antidromic stimulation of the cervical dorsal columns and stained intracellularly with horseradish peroxidase. The cell bodies were located in laminae III-IV. Their dendritic arbors were elongated rostrocaudally but narrow mediolaterally. On the average, the arbors were X 5 longer than they were wide. Most of the neurons had nearly all of their dendrites in laminae III-IV and some of the neurons had, in addition, a considerable amount of dendritic surface area in lamina V. Only one neuron had more than a very small amount of dendritic surface area dorsal to lamina III. Seven of the neurons had unmyelinated axon collaterals that arborized extensively and issued varicosity-bearing terminal branches in laminae III-V, both within and beneath their dendritic territories. All of the neurons were excited by myelinated, low-threshold mechanoreceptors. Since the rostrocaudally elongated and mediolaterally narrow dendritic arbors of DCPS neurons are in register with the laminae III-IV terminal distributions of myelinated, low-threshold mechanoreceptors, it is probable that this excitation arises from a monosynaptic and topographically discrete innervation. About one-half of the DCPS neurons were also excited by noxious stimuli. It is probable that this excitation is accomplished by a polysynaptic pathway since DCPS dendritic arbors and nociceptor terminal distributions are largely or completely separate.

Cells of origin of the spinoreticular tract in the monkey.

The distribution of the cells of origin of the primate spinoreticular tract was determined following injections of horseradish peroxidase (HPR) into the pontomedullary reticular formation in Macaca fascicularis. Five animals received large bilateral injections which included the raphe nuclei and seven monkeys received smaller, unilateral injections. Sections sampled were from upper cervical levels, the cervical enlargement, upper and lower thoracic levels, and lumbosacral levels. The laminar distribution of spinoreticular cells in all spinal cord levels was comparable. More than half of the labeled cells were located ventromedially, in laminae VII and VIII. HRP-labeled cells were also found in the dorsal horn, primarily in the lateral reticulated part of lamina V. Some cells were also found in laminae I and X. Spinoreticular cells in the lumbosacral spinal cord mainly projected to the contralateral brainstem. In the cervical enlargement, however, a bilateral distribution of cells was observed following unilateral injections of HRP. Most spinoreticular cells were multipolar neurons with extensive dendritic ramifications. The distribution of spinoreticular cells is similar to the distribution of spinal cord neurons that project to the medial thalamus, but different from that of spinal neurons projecting to the ventrobasal complex. The anatomical organization of the spinoreticular tract is consistent with a role for this pathway in nociception.

Immunohistochemical localization of leucine-enkephalin in the spinal cord of the cat: enkephalin-containing marginal neurons and pain modulation.

This study examined the spinal cord distribution of the endogenous opioid peptide leucine-enkephalin in the cat using immunohistochemical techniques. The distribution of nerve processes was studied in untreated cats; colchicine was administered to study the distribution and morphology of spinal enkephalin-containing perikarya. Enkephalin immunoreactive processes were greatest in laminae I and II (marginal layer and substantia gelatinosa) of the superficial dorsal horn. In many sections, the outer substantia gelatinosa (SG), lamina IIa, was discernibly less immunoreactive than I or IIb. Laminae III and IV were relatively devoid of staining. Laminae V and VII had moderate enkephalin-immunoreactivity, lamina VI somewhat less. Enkephalin immunoreactivity in lamina X, around the central canal, was very dense. Enkephalin-containing beaded varicosities coursed throughout the ventral horn. Although previous studies in the rat emphasized the enkephalin-somata of the SG, we found that in the cat the majority of superficial dorsal horn enkephalin-somata are in the marginal layer. These enkephalin-containing marginal cells were morphologically similar to a population of marginal neurons which project to the brainstem and/or the thalamus. Some light staining small SG neurons were also identified; many were located at the lamina I-II border. Considerably more cells were found ventral to the SG, in lamina III, and at the IV-V border. These latter cells had dendrites coursing dorsally, toward the SG. Numerous immunoreactive cells were found in lamina VIII, in a band across the intermediate gray. These cells fused medially with cells of lamina X. Enkephalin cells were also found in the sacral autonomic nucleus and encircling the central cervical nucleus, Clarke's column, and stilling's nucleus. Although surrounded by labeled cells, the latter regions were devoid of enkephalin-immunoreactive processes. Many of these spinal enkephalin neurons are morphologically similar to and distributed in regions known to contain projection neurons. Thus it is suggested that many spinal enkephalin neurons, generally thought to be local circuit neurons, project rostrally, to other spinal levels and perhaps to brainstem and/or thalamus.

Trigeminal nociceptive neurons in the subnucleus reticularis ventralis. I. Response properties and afferent connections.

Trigeminal nociceptive neurons within the subnucleus reticularis ventralis medullae oblongatae (SRV), which lies ventral to the trigeminal subnucleus caudalis and subnucleus reticularis dorsalis medullae oblongatae, were studied in urethane/chloralose-anesthetized cats and monkeys. These neurons were called 'SRV neurons'. They were almost regularly excited by pressure to the ipsilateral cornea or to both corneas at a strength well above the human corneal pain threshold. Most of them were activated by noxious mechanical stimulation of the pinna, face and/or tongue. A significant fraction of SRV units was responsive to tapping of the ipsilateral dorsum of the nose and/or electrical stimulation of tooth pulp afferents. Evidence was obtained that responses to tapping of the dorsum of the nose were due to mechanical distortion of the nasal mucosa. Intracellular injection of HRP into SRV neurons demonstrated that injected neurons were large neurons characteristic of the SRV. Trigeminal tractotomy just rostral to the obex did not eliminate responses of SRV units to trigeminal inputs. Neurons relaying trigeminal inputs to SRV neurons were electrophysiologically identified in the nucleus reticularis parvocellularis which is ventromedially adjacent to the subnuclei oralis and interpolaris of the trigeminal spinal tract nucleus. These findings were supported by HRP injection into the SRV. Units having receptive fields similar to those of SRV neurons were found in lamina VII of the first cervical cord, suggesting that SRV neurons may be trigeminal lamina VII neurons.

A treatment algorithm for neuropathic pain.

BACKGROUND: Neuropathic pain is a chronic pain syndrome caused by drug-, disease-, or injury-induced damage or destruction of sensory neurons within the dorsal root ganglia of the peripheral nervous system. Characteristic clinical symptoms include the feeling of pins and needles; burning, shooting, and/or stabbing pain with or without throbbing; and numbness. Neuronal hyperexcitability represents the hallmark cellular mechanism involved in the underlying pathophysiology of neuropathic pain. Although the primary goal is to alleviate pain, clinicians recognize that even the most appropriate treatment strategy may be, at best, only able to reduce pain to a more tolerable level. OBJECTIVE: The purpose of this review is to propose a treatment algorithm for neuropathic pain that health care professionals can logically follow and adapt to the specific needs of each patient. The algorithm is intended to serve as a general guide to assist clinicians in optimizing available therapeutic options. METHODS: A comprehensive review of the literature using the PubMed, MEDLINE, Cochrane, and Toxnet databases was conducted to design and develop a novel treatment algorithm for neuropathic pain that encompasses agents from several drug classes, including antidepressants, antiepileptic drugs, topical antineuralgic agents, narcotics, and analgesics, as well as various treatment options for refractory cases. RESULTS: Any of the agents in the first-line drug classes (tricyclic antidepressants, antiepileptic drugs, topical antineuralgics, analgesics) may be used as a starting point in the treatment of neuropathic pain. If a patient does not respond to treatment with at least 3 different agents within a drug class, agents from a second drug class may be tried. When all first-line options have been exhausted, narcotic analgesics or refractory treatment options may provide some benefit. Patients who do not respond to monotherapy with any of the first- or second-line agents may respond to combination therapy or may be candidates for referral to a pain clinic. Because the techniques used at pain clinics tend to be invasive, referrals to these clinics should be reserved for patients who are truly refractory to all forms of pharmacotherapy. CONCLUSIONS: Neuropathic pain continues to be one of the most difficult pain conditions to treat. With the proposed algorithm, clinicians will have a framework from which to design a pain treatment protocol appropriate for each patient. The algorithm will also help streamline referrals to specialized pain clinics, thereby reducing waiting list times for patients who are truly refractory to traditional pharmacotherapy.

Characterization of the primary spinal afferent innervation of the mouse colon using retrograde labelling.

Visceral pain is the most common form of pain produced by disease and is thus of interest in the study of gastrointestinal (GI) complaints such as irritable bowel syndrome, in which sensory signals perceived as GI pain travel in extrinsic afferent neurones with cell bodies in the dorsal root ganglia (DRG). The DRG from which the primary spinal afferent innervation of the mouse descending colon arises are not well defined. This study has combined retrograde labelling and immunohistochemistry to identify and characterize these neurones. Small to medium-sized retrogradely labelled cell bodies were found in the DRG at levels T8-L1 and L6-S1. Calcitonin gene-related peptide (CGRP)- and P2X3-like immunoreactivity (LI) was seen in 81 and 32%, respectively, of retrogradely labelled cells, and 20% bound the Griffonia simplicifolia-derived isolectin IB4. CGRP-LI and IB4 were co-localized in 22% of retrogradely labelled cells, whilst P2X3-LI and IB4 were co-localized in 7% (vs 34% seen in the whole DRG population). Eighty-two per cent of retrogradely labelled cells exhibited vanilloid receptor 1-like immunoreactivity (VR1-LI). These data suggest that mouse colonic spinal primary afferent neurones are mostly peptidergic CGRP-containing, VR1-LI, C fibre afferents. In contrast to the general DRG population, a subset of neurones exist that are P2X3 receptor-LI but do not bind IB4.

Ascending projections to nucleus parafascicularis of the cat.

Experiments utilizing the retrograde transport of horseradish peroxidase (HRP) were performed in order to locate the cells of origin of ascending projections to the parafascicular nucleus (Pf) of the cat. HRP-labelled cells were identified in several regions of the brain stem including: trigeminal nuclei, vestibular nuclei, nucleus coeruleus, tegmental field, deep layers of the superior colliculus, substantia nigra, dorsal median nucleus of Raphe and periaqueductal grey substance. Of these, the periaqueductal grey contained approximately 40% of labelled neurones. A weak spinal cord projection to Pf originated bilaterally from laminae VI and VII-VIII at C1 and C2 and some neurones were also found contralaterally at C7 and L7.

Collateralization in the spinothalamic tract: new methodology to support or deny phylogenetic theories.

Components of the spinothalamic system that ascend in the anterolateral funiculus are reviewed. The presence of collateralization in this system in mammals is discussed with regard to theories of the phylogenetic development of pathways. The major theory investigated suggested that collateralization is an intermediate stage between a multisynaptic pathway and a direct non-collateralized lemniscus. The evidence and theories are reviewed. Methods for confirming or rejecting this theory are discussed. The literature reporting ascending spinal projections for non-mammalian vertebrates is reviewed. Certain reptiles have projections analogous to both the mammalian neospinothalamic and paleospinothalamic tracts. The presence of spinothalamic projections in elasmobranchs and amphibians is still controversial. Confirmation of earlier reports of projections in salamander and dogfish shark based on degeneration techniques have not been done. In addition, results from too few species of these classes have been reported. However, it is possible that paleospinothalamic connections are present in some species (e.g. salamander, nurse shark) and not in others (e.g. frog, dogfish shark) of the same class. Spinothalamic projections have not been reported for teleosts. A plea for new research in this area is made.

Multiple afferent innervation of primate facial hairs--Henry Head and Max von Frey revisited.

Large guard hairs as well as small vellus hairs are multiple innervated having lanceolate terminals of variable number. Ruffini corpuscles consisting of fine axonal ramifications are arranged circularly and located external to the lanceolate terminals. Free nerve endings (FNE's) can also be identified on some hairs distinct from Ruffini terminals. Ruffini terminals and FNE's are usually innervated by axons from the superficial dermal nerve net whereas lanceolate terminals are innervated by axons from the deeper portions of the dermal nerve net. All guard hairs have both types of terminals (lanceolate and Ruffini) confirming Hoggan and Hoggan, Retzius and Symonowicz, and most guard hairs have presumptive FNE's. Many vellus hairs have only small Ruffini endings or FNE's. The diameter of axons supplying Ruffini terminals is 1-2 micrometer and those to lanceolate terminals is 2-4 micrometers. Axons innervating lanceolate and Ruffini terminals branch rarely as correlated with small punctate receptive fields. FNE's branch widely and are correlated with large receptive fields of known nociceptors. The multiplicity of anatomically defined terminals is consistent with the known diversity of physiologically defined hair mechanoreceptive afferents as well as perceptual complexity of human hairy skin. The concept of multiple innervation of hairs confirms Head's prediction and could provide the anatomical basis of Head's basic thesis of altered sensibilities in nerve regeneration (i.e. epicritic and protopathic responses). Head's concept of two separate nervous systems, however, is an over-simplification in the light of current knowledge.

The periaqueductal gray-raphe magnus projection contains somatostatin, neurotensin and serotonin but not cholecystokinin.

The retrograde transport-HRP-immunocytochemical technique was employed to ascertain if the periaqueductal gray-raphe magnus projection arises from neurons containing somatostatin, neurotensin, serotonin or cholecystokinin. Following HRP injections into the raphe magnus (NRM) double-labeled cells containing HRP reaction product and somatostatin-, neurotensin- or serotonin-like immunoreactivity were identified in the midbrain periaqueductal gray (PAG). No cholecystokinin-like immunoreactive double-labeled neurons were found in the PAG. These results indicate that the PAG-NRM pathway contains somatostatin, neurotensin and serotonin but not cholecystokinin.

Neuroanatomy of the pain system and of the pathways that modulate pain.

We review many of the recent findings concerning mechanisms and pathways for pain and its modulation, emphasizing sensitization and the modulation of nociceptors and of dorsal horn nociceptive neurons. We describe the organization of several ascending nociceptive pathways, including the spinothalamic, spinomesencephalic, spinoreticular, spinolimbic, spinocervical, and postsynaptic dorsal column pathways in some detail and discuss nociceptive processing in the thalamus and cerebral cortex. Structures involved in the descending analgesia systems, including the periaqueductal gray, locus ceruleus, and parabrachial area, nucleus raphe magnus, reticular formation, anterior pretectal nucleus, thalamus and cerebral cortex, and several components of the limbic system are described and the pathways and neurotransmitters utilized are mentioned. Finally, we speculate on possible fruitful lines of research that might lead to improvements in therapy for pain.

Pain perception and response: central nervous system mechanisms.

Although several decades of studies have detailed peripheral and ascending nociceptive pathways to the thalamus and cerebral cortex, pain is a symptom that has remained difficult to characterize anatomically and physiologically. Positron emission tomography (PET) and functional magnetic imaging (fMRI) have recently demonstrated a number of cerebral and brain stem loci responding to cutaneous noxious stimuli. However, intersubject variability, both in the frequency and increased or decreased intensity of the responses, has caused uncertainty as to their significance. Nevertheless, the large number of available imaging studies have shown that many areas with recognized functions are frequently affected by painful stimuli. With this evidence and recent developments in tracing central nervous system connections between areas responding to noxious stimuli, it is possible to identify nociceptive pathways that are within, or contribute to, afferent spino-thalamo-cortical sensory and efferent skeletomotor and autonomic motor systems. In this study it is proposed that cortical and nuclear mechanisms for pain perception and response are hierarchically arranged with the prefrontal cortex at its highest level. Nevertheless, all components make particular contributions without which certain nociceptive failures can occur, as in pathological pain arising in some cases of nervous system injury.

Pain: its physiology and rationale for management. Part I. Neuroanatomical substrate of pain.

Pain, one of man's most worrisome afflictions, is also one of neurobiology's most challenging problems. Even its definition is beset with controversy. The origin and current resolution of this controversy are presented in this paper, but the major purpose of Part I is to review the anatomical substrate of the peripheral and central nervous systems involved in pain. Structural and functional characteristics of pain receptors and their afferent fibers are described, with emphasis upon current hypotheses regarding putative neural transmitters and possible mechanisms for signal transduction. Hitherto unrecognized details of the cytoarchitecture, anatomical organization, and circuitry of the dorsal horns are reviewed. The paper concludes with a consideration of the major components of the ascending and descending systems of subserving pain.

[The dorsal root entry zone of the spinal cord: the surgical target in the treatment of pain and spasticity]. / La zone d'entrée des racines postérieures dans la moelle: cible chirurgicale pour le traitement de la douleur et de la spasticité.

The large amount of experimental works performed in the 60s and 70s, demonstrating the important role of DREZ in the modulation of the segmental mechanisms of pain and spasticity, drew the author's attention to this site as a possible target for surgery. The anatomical rationale, techniques and results of the procedure, named microsurgical -DREZ-tomy, are developed.

[Some useful basics of functional anatomy for a better understanding of the pain phenomenon]. / Quelques rappels d'anatomie fonctionnelle utiles à la compréhension du phénomène douloureux.

Cannot simply be considered as a nociception phenomenon: it is more complex than a simple transmission system that conveys this information to the cerebral cortex. It is mainly a psychological event. Numerous regulating and inhibiting effects on incoming pain signals exist, for the most part located in spinal and thalamic areas; only half of these are morphine-dependent. Knowledge of these allows a better approach to chronic pain, using not only medication but also other techniques such as physiotherapy and music therapy analgesia.