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.

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.

Correlation of functional activation in the rat spinal cord with neuronal activation detected by immunohistochemistry.

The relationship between neuronal activity in the rat cervical and lumbar spinal cord was examined using functional magnetic resonance imaging (fMRI) and immunohistochemistry. Neuronal activity determined by c-fos staining was greatest between L4 and L6, and C5 to C7 spinal cord segments during noxious electrical stimulation of the rat hindpaw and forepaw, respectively. Areas of activity determined by fMRI are consistent with spinal cord physiology, and are predominantly found in regions of the spinal cord associated with pain, namely the dorsal horn. Activity in the ventral region of the cord was also observed, as expected. Combined results from repeated experiments demonstrated consistent areas of activity in response to stimulation, and show a high degree of reproducibility. Good correspondence was observed between functional MRI and sites of neuronal activity determined by c-fos labeling.

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.

Encoding of location and intensity of noxious indentation into rat skin by spatial populations of cutaneous mechano-nociceptors.

The ability of a spatial population of cutaneous, Adelta, and C mechano-nociceptors to encode the location and intensity of a noxious, cutaneous indentation was examined using an isolated preparation in a rat model. Skin and its intact innervation were harvested from the medial thigh of the rat hindlimb and placed in a dish, with the corium side down, containing synthetic interstitial fluid. The margins of the skin were coupled to an apparatus that could stretch and apply compression to the skin. The skin was suspended on top of a deformable platform whose bulk, nonlinear, compressive compliance emulated that found in vivo. The isolated preparation facilitated examination of the spatial population response by eliminating the nonlinear geometry and inhomogeneous compressive compliance present in-vivo. Spatial population responses (SPR) were formed from recordings of single neurons that were stimulated by compressing the skin with an indenter (flat cylinder, 3-mm diam) at discrete intervals from the center of their receptive fields. SPR were composed of the neural responses (z axis) at each indentation location (x, y plane), and were analyzed quantitatively using nonlinear regression to fit an equation of a Gaussian surface. Both Adelta and C SPR accurately encoded the location and intensity of noxious indentation. The intensity of the stimulus was encoded in the peak neural response of the SPR, which had a nonlinear relationship to the compressive force. The location of the stimulus was encoded in the x, y position of the peak of the SPR. The position of the peak remained constant with increasing magnitudes of compressive force. The overall form of the SPR also remained constant with changes of compressive load, suggesting a possible role for encoding in the SPR some aspects of shape of a noxious stimulus.

Innervation of nociceptors in the menisci of the knee joint: an immunohistochemical study.

Using histology, we studied the innervation of nociceptors in the medial and lateral menisci of the knee joint. Specimens examined were taken from 16 patients during arthroplasty. The patients were 6 men and 10 women, with ages ranging from 14 to 76 years (mean 56 years). Immunohistochemistry with the unlabeled antibody biotin-streptavidin method was employed to detect protein gene product 9.5 (PGP 9.5) or substance P (SP) in the specimen. The antibody for PGP 9.5 detected nerve tissues in the menisci. Most but not all of the nerve fibers were associated with blood vessels. Nerve fibers and sensory receptors were found mainly in the peripheral, vascular zone, representing the outer one-third of the meniscus, and the innervated area was wider in the anterior and posterior horns. Pacinian and Ruffini corpuscles as well as free nerve endings were identified in these areas. Larger fibers coursed circumferentially in the peripheral zone, with smaller branches of nerve fibers running radially into the meniscus. Nerve fibers positive for SP were also detected in the menisci, but were fewer in number. Their branches also were fewer, oriented radially and paralleling blood vessels. This study showed that some of the pain in cases of meniscal tear could originate in the meniscus itself, especially with peripheral tears that may be accompanied by bleeding.

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.

A morphometric analysis of protein gene product 9.5-, substance P-, and calcitonin gene-related peptide immunoreactive innervation in the shoulder joint of the Japanese macaque.

The shoulder capsule and labrum of Japanese macaque monkeys were studied immunohistochemically with the use of antisera against protein gene product 9.5 (PGP 9.5), calcitonin gene-related peptide (CGRP), and substance P (SP) to further characterize the innervation of the supporting structures of the shoulder joint. With PGP 9.5 immunohistochemistry thick nerve fibers (diameter > or = 10 microm) presumed to be proprioceptive based on topographic location were found to be abundant in the posterior half of the capsule. Thinner fibers (diameter <10 microm) presumed to contain nociceptive and autonomic fibers were located in the posterior half of the capsule. Ruffini-like corpuscles were predominantly located in the inferior portion of the capsule. SP and CGRP immunoreactive thin fibers presumed to be nociceptive were abundant in the posterior half of the capsule. Thin fibers that appeared to be nociceptive fibers were found in the marginal portion and the parenchyma of the labrum, although the number was small. The predominant distribution of the Ruffini-like corpuscles in the inferior portion of the capsule suggest an important role of the inferior portion in generation of the proprioceptive output, which should be advantageous in stabilization of the joint in motion. The abundance of nociceptive fibers in the posterior half of the capsule may be responsible for the pathophysiological transmission of pain around the shoulder joint.

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.

[Projections and fiber characteristics of sensory afferents of the anterior cruciate ligament in an animal experiment]. / Projektion und Faserqualität der sensiblen Afferenzen aus dem vorderen Kreuzband im Tierexperiment.

The sensory innervation of the rabbit anterior cruciate ligament was studied by retrograde tracing technique using wheat-germ-agglutinin-horseradish-peroxidase (WGA-HRP) and Fast Blue as neuronal tracers. Injection of the tracer into the ligament was followed by histo- and immunohistochemical investigation of labelled nerve cell bodies located in the dorsal root ganglia. In 4 animals we injected the tracer into the joint cavity to label general joint afferents. The segmental distribution of retrogradely labelled neurons following injection into the anterior cruciate ligament (L6, L7, S1) is significantly different from the distribution pattern after injection into the knee joint (L4-S2). Retrogradely labelled nerve cells innervating the anterior cruciate ligament were further investigated using immunohistochemical and morphometric analysis. The sensory innervation of the anterior cruciate ligament is therefore comprised of at least 2 different qualities of sensory afferent nerves: 1. Small neurones immunoreactive to the inflammatory peptide substance P most likely transmitting nociceptive information centrally (44%). 2. Large, presumably fast conducting A-fibre-afferents characterized by neurofilament proteins transmitting proprioceptive information from corpuscular mechanoreceptors (43%). The results of this study put further weight to the importance of the sensory role of the anterior cruciate ligament using neuroanatomical and immunohistochemical techniques.

The sensory biology of the living jawless fishes: a phylogenetic assessment.

Despite the ancient origins and aberrant appearance of living jawless fishes, none of their features may be assumed to be primitive without comparisons among hagfishes, lampreys, and gnathostomes, and with the nearest relatives of all craniates, the cephalochordates. In this review, the sensory capabilities of lampreys and hagfishes will be compared, and the major features of early craniate sensory evolution will be infered using cladistic methodology and an accepted phylogeny of the hagfishes, lampreys and gnathostomes. Lampreys have well developed olfactory, visual and octavolateralis systems, each of which is known to play a role in lamprey life and behavior. Hagfishes have poorly developed visual and octavolateralis systems, but elaborate olfactory and chemosensory systems. Unfortunately, the natural behavior and lifestyle of hagfishes are poorly known, limiting our understanding of hagfish sensory biology. Both groups of living jawless fishes show mixtures of primitive and secondarily derived sensory features and have few shared derived sensory features that would indicate close relations between the two groups.

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.

[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.

Hypoglossal afferents to lamina I neurons of the cervical spinal cord projecting to the parabrachial nucleus in the cat.

Attempts were made to determine the hypoglossal sensory inputs to the parabrachial nucleus (PBN) through the spinal cord. Wheatgerm agglutinin conjugated to horseradish peroxidase (WGA:HRP) was injected into the cat hypoglossal nerve. HRP-labeled fibers, predominantly derived from the glossopharyngeal and vagal nerves, were observed to terminate in lamina I of the upper cervical spinal cord. A few fibers were also distributed to laminae IV-V and VII-VIII ipsilaterally. WGA:HRP injection into the lateral portion of the PBN also resulted in retrograde labeling in lamina I with ipsilateral predominance. Light-microscopic data raised the possibility of a relay of hypoglossal sensory information to the PBN in lamina I of the cervical spinal cord. In order to confirm the spinal relay, electron-microscopic observations were carried out on lamina I of C1 spinal cord after sectioning of the hypoglossal nerve and WGA:HRP injection into the lateral portion of the PBN on the same side in each animal. It was of particular interest that degenerated hypoglossal afferent fibers made synaptic contacts with lamina I neurons, which were retrogradely labeled with HRP.

Calcitonin gene-related peptide and peripherin immunoreactivity in nerve sheaths.

The intrinsic innervation of rat sciatic nerve sheaths was studied by means of immunohistochemical labeling for calcitonin gene-related peptide (CGRP) and peripherin. CGRP immunoreactivity (CGRP-IR) and peripherin immunoreactivity (peripherin-IR) were found in fine nerve fibers independent of nerve sheath vasculature. These findings suggest that a subset of the nervi nervorum may have nociceptive functions, and that this subset is distinct from nerve fibers that innervate the blood vessels of the nerve sheaths.

Squirrel monkey lateral thalamus. I. Somatic nociresponsive neurons and their relation to spinothalamic terminals.

The incidence and response properties of nociresponsive neurons, their locations relative to spinothalamic terminals, and their relations to cytoarchitectonic borders were studied in the lateral thalamus of the squirrel monkey. Nociceptive neurons were found in ventral posterior inferior nucleus (VPI), in the lateral and medial nuclei (VPL and VPM) of the ventral posterior complex (VP = VPL + VPM), as well as the posterior complex (PO). The overall incidence of nociresponsive cells was 19% (50 of 270 cells). The proportion of nociresponsive neurons within VPI was 50% (23 of 46), 38% in PO (8 of 21), and 10% in VP (19 of 203). Most nociresponsive cells (90%) in VP were of wide-dynamic-range type, while within VPI 43% of nociresponsive cells were nociceptive-specific type. Most of these nociresponsive cells had thermal and mechanical responses, and a small number also responded to cooling. The receptive fields of nociresponsive cells in VPL were in continuity, in both size and body location, with surrounding low-threshold units. The receptive fields of VPI and PO nociresponsive cells were larger than those in VPL. The probability of encountering nociresponsive cells located within 100 microns of spinothalamic terminations was high in VPI (73%) and low in VPL (33%). On the other hand, the probability of encountering non-nociceptive cells located within 100 microns of spinothalamic terminals was low in both VPI (20%) and VPL (26%). The results indicate segregation of nociresponsive cell types across VP, VPI, and PO and suggest that VPI, and perhaps PO, is an important region for discriminative processing and perception of painful stimuli.