OBJECTIVE-To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. METHODS-Inflammatory mediators (IM)were applied to the dura of unanesthetized rats via previously implanted cannulas and sensory thresholds of the face and hindpaws were characterized.RESULTS-IM elicited robust facial and hindpaw allodynia which peaked within 3 hr. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in treatment of migraine, including sumatriptan, naproxen, and a CGRP-antagonist. Consistent with clinical observations the allodynia was unaffected by an NK-1 antagonist. Having established facial and hindpaw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM ON cells and transient suppression of RVM OFF cells following IM.INTERPRETATION-Facial and hindpaw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia and are consistent with a brainstem generator of allodynia associated with headache disorders.
Previous studies in the macaque monkey have identified a thalamic nucleus, the posterior portion of the ventral medial nucleus (VMpo), as a dedicated lamina I spinothalamocortical relay for pain and temperature sensation. The dense plexus of calbindin-immunoreactive fibres that characterizes VMpo in primates enables its homologue to be identified in the human thalamus by immunohistochemical labelling for calbindin. We have now analysed in detail the cytoarchitectonic characteristics of VMpo and its relationship with immunoreactivity for calbindin, substance P and calcitonin gene-related peptide (CGRP) in the human thalamus. The area in the posterolateral thalamus in which dense calbindin-immunoreactive fibre terminations are present coincides nearly completely with a distinct region that contains small to medium-sized cells with round or oval shapes that are aggregated in clusters separated by cell sparse areas. This region, which we identify as VMpo, is located posteromedial to the ventral posterior lateral (VPL) and ventral posterior medial (VPM) nuclei, ventral to the anterior pulvinar and centre médian nuclei, lateral to the limitans and parafascicular nuclei and dorsal to the medial geniculate nucleus. Calbindin-immunoreactive fibres enter VMpo from the spinal lemniscus and form large patches of dense terminal-like staining over clusters of VMpo neurons. A few of these clusters also display terminal-like substance P labelling. Small bursts of CGRP staining are intercalated between the calbindin-labelled clusters, but there is little or no overlap between these two markers. CGRP immunoreactivity is also present over small, non-clustered neurons in the calbindin-negative area that separates VMpo from the VPL and VPM nuclei, which we denote as the posterior nucleus (Po). These observations provide a concise description of VMpo in the human thalamus. Further, they suggest that the lamina I spinothalamic tract fibres (represented by calbindin and probably also substance P immunoreactivity) and vagal-solitary-parabrachial afferents (represented by CGRP immunoreactivity) form closely related, but separate, termination fields that can be considered to represent different aspects of enteroceptive information regarding the physiological status of the tissues and organs of the body. The location of VMpo and the adjacent Po fits with clinical descriptions of the thalamic area from which pain, temperature and visceral sensations can be evoked by microstimulation, and where nociceptive and thermoreceptive neurons have been recorded in humans. It also corresponds to the area in which infarcts cause analgesia and thermoanaesthesia and can lead to the paradoxical development of central pain.
Lamina I spinothalamic tract (STT) neurons were identified by retrograde labeling with cholera toxin subunit b (CTb) in monkeys. On the basis of the criteria of somatal shape and dendritic orientation in horizontal sections used in prior work in the cat, three distinct morphological types were recognized: fusiform (F) cells with spindle-shaped somata and two main longitudinal dendritic arbors; pyramidal (P) cells with triangular somata and three main dendrites oriented primarily longitudinally; and multipolar (M) cells with polygonal somata and four or more dendrites directed longitudinally and mediolaterally. Some cells had transitional shapes, but cells with indeterminate shapes and a few with small round, unipolar, or eccentric somata were grouped as unclassified (U). Greater variation appeared in the monkey than had been seen in the cat, and more subtypes were noted. The overall proportions of these cell types were: 47% F, 27% P, 22% M, and 5% U. Differential longitudinal distributions were found over the length of the spinal cord (from the second cervical through the first coccygeal segments). Pyramidal and multipolar cells together predominated in the enlargements, whereas fusiform cells predominated in thoracic segments. We conclude that three distinct morphological types of lamina I STT cells are present in the monkey as in the cat. Considered with other recent findings, the present results support the possibility that these three cell types may correspond to distinct physiological classes of nociceptive and thermoreceptive lamina I STT cells.
The distribution of retrogradely labeled spinothalamic tract (STT) neurons was analyzed in macaque monkeys following variously sized, physiologically guided pressure or iontophoretic injections of cholera toxin subunit B (CTb) in order to determine whether different STT termination sites receive input selectively from different sets of STT cells. This report focuses on posterolateral thalamus, where prior anterograde tracing observations identified the posterior part of the ventromedial nucleus (VMpo) as the major projection target of lamina I STT neurons. Large injections in posterolateral thalamus labeled predominantly STT cells in lamina I throughout the spinal cord. In cases with medium-sized or small injections centered in VMpo, almost all labeled STT cells ( approximately 90%) were lamina I neurons. Small injections revealed a posteroanterior (foot to hand) somatotopographic organization consistent with that observed in prior anterograde tracing work; injections in posterior VMpo labeled primarily lumbosacral lamina I cells, whereas injections placed more anteriorly in VMpo labeled primarily cervical lamina I cells. These findings support the concept that VMpo is a primate lamina I spinothalamocortical relay nucleus important for pain, temperature, itch, muscle ache, sensual touch, and other interoceptive feelings from the body, and they provide strong evidence for the general hypothesis that the STT consists of several functionally and anatomically differentiable components.
We examined the morphology and distribution of retrogradely labeled spinothalamic tract (STT) neurons in lamina I (the marginal zone) of the spinal dorsal horn after large injections of cholera toxin subunit B (CTb) or Fast Blue (FB) into the contralateral thalamus of cats. Based on the shape and orientation of the somata and proximal dendrites in horizontal sections, three distinct cell types were identified: (1) fusiform cells with small, spindle-shaped somata and bipolar, longitudinal dendritic arbors; (2) pyramidal cells with triangular somata and three main dendritic origins with primarily longitudinal arborizations; and (3) multipolar cells with larger, multiangular somata and four or more radiating dendritic arbors directed both longitudinally and mediolaterally. These three morphological types differed significantly in the number of primary dendrites and the size of the somata. Subclasses of multipolar cells were noted. Nearly all cells could be categorized into these three classes consistently in horizontal sections. A small number of cells with transitional shapes or with small, round somata were unclassified. The proportional distributions of these cell types were found to vary over the length of the spinal cord (from the third cervical through the coccygeal segments) in three cats. The overall proportions of cell types were 34% fusiform, 36% pyramidal, 25% multipolar, and 5% unclassified. The proportions of pyramidal and multipolar cells were strikingly higher within the C7-8 and L6-7 segments and lowest in the thoracic segments. In contrast, fusiform cells formed about 20% of the labeled lamina I STT population in the C7-8 and L6-7 segments but more than 60% in thoracic segments. Across all nine cats, the proportions were similar within the cervical (C5-8) and lumbosacral (L5-S1) enlargements, although considerable interanimal variability was noted. These distinct morphological types of lamina I STT cells with differential longitudinal distributions probably have different functional roles. They may correspond to the three main physiological classes of lamina I STT cells.
An immunohistochemically distinct zone was identified in the superficial aspect of trigeminal nucleus caudalis of the New World owl monkey that is not immunoreactive for substance P or serotonin, in stark contrast to the dense staining present in the surrounding laminae I and II. Thionin-stained sections in different planes showed that this is a subregion of lamina I containing clusters of neurons that appear to have pyramidal or polygonal somata. Extracellular microelectrode recordings in this region revealed clusters of thermoreceptive-specific (COLD) cells with nasal or labial receptive fields, whereas nociceptive neurons were found in the adjacent portions of lamina I. Anterograde tracer injections in this region produced trigeminothalamic terminal labeling in the site homologous to the lamina I spino-thalamo-cortical relay nucleus identified previously in the Old World macaque monkey and in humans. Retrograde tracer injections involving this thalamic site, where recordings of trigeminal COLD-like neurons were obtained, produced clusters of retrogradely labeled trigeminothalamic neurons in this immunohistochemically distinct subregion of lamina I, nearly all of which are pyramidal neurons. We conclude that the nocturnal owl monkey has a specialized perinasal thermoreceptive trigeminothalamic sensory pathway that is probably of behavioral significance during olfactory sniffing. In addition, these observations corroborate other findings that have indicated that lamina I COLD cells are pyramidal neurons and are not physiologically modulated by substance P or serotonin, in contrast to nociceptive neurons.
We examined the morphology and distribution of retrogradely labeled spinothalamic tract (STT) neurons in lamina I (the marginal zone) of the spinal dorsal horn after large injections of cholera toxin subunit B (CTb) or Fast Blue (FB) into the contralateral thalamus of cats. Based on the shape and orientation of the somata and proximal dendrites in horizontal sections, three distinct cell types were identified: (1) fusiform cells with small, spindle-shaped somata and bipolar, longitudinal dendritic arbors; (2) pyramidal cells with triangular somata and three main dendritic origins with primarily longitudinal arborizations; and (3) multipolar cells with larger, multiangular somata and four or more radiating dendritic arbors directed both longitudinally and mediolaterally. These three morphological types differed significantly in the number of primary dendrites and the size of the somata. Subclasses of multipolar cells were noted. Nearly all cells could be categorized into these three classes consistently in horizontal sections. A small number of cells with transitional shapes or with small, round somata were unclassified. The proportional distributions of these cell types were found to vary over the length of the spinal cord (from the third cervical through the coccygeal segments) in three cats. The overall proportions of cell types were 34% fusiform, 36% pyramidal, 25% multipolar, and 5% unclassified. The proportions of pyramidal and multipolar cells were strikingly higher within the C7-8 and L6-7 segments and lowest in the thoracic segments. In contrast, fusiform cells formed about 20% of the labeled lamina I STT population in the C7-8 and L6-7 segments but more than 60% in thoracic segments. Across all nine cats, the proportions were similar within the cervical (C5-8) and lumbosacral (L5-S1) enlargements, although considerable interanimal variability was noted. These distinct morphological types of lamina I STT cells with differential longitudinal distributions probably have different functional roles. They may correspond to the three main physiological classes of lamina I STT cells.
An immunohistochemically distinct zone was identified in the superficial aspect of trigeminal nucleus caudalis of the New World owl monkey that is not immunoreactive for substance P or serotonin, in stark contrast to the dense staining present in the surrounding laminae I and II. Thionin‐stained sections in different planes showed that this is a subregion of lamina I containing clusters of neurons that appear to have pyramidal or polygonal somata. Extracellular microelectrode recordings in this region revealed clusters of thermoreceptive‐specific (COLD) cells with nasal or labial receptive fields, whereas nociceptive neurons were found in the adjacent portions of lamina I. Anterograde tracer injections in this region produced trigeminothalamic terminal labeling in the site homologous to the lamina I spino‐thalamo‐cortical relay nucleus identified previously in the Old World macaque monkey and in humans. Retrograde tracer injections involving this thalamic site, where recordings of trigeminal COLD‐like neurons were obtained, produced clusters of retrogradely labeled trigeminothalamic neurons in this immunohistochemically distinct subregion of lamina I, nearly all of which are pyramidal neurons. We conclude that the nocturnal owl monkey has a specialized perinasal thermoreceptive trigeminothalamic sensory pathway that is probably of behavioral significance during olfactory sniffing. In addition, these observations corroborate other findings that have indicated that lamina I COLD cells are pyramidal neurons and are not physiologically modulated by substance P or serotonin, in contrast to nociceptive neurons. J. Comp. Neurol. 404:221–234, 1999. © 1999 Wiley‐Liss, Inc.
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