Cerebral arterial innervation by nerve fibers containing calcitonin gene-related peptide (CGRP): I. Distribution and origin of CGRP perivascular innervation in the rat

The origin, density and distribution of calcitonin gene-related peptide (CGRP) immunoreactivity in cerebral perivascular nerves and the trigeminal ganglion of rats were examined in this study. CGRP immunoreactive axons were abundant on the walls of the rostral circulation of the major cerebral arteries in the circle of Willis. The fibers form a grid- or meshwork of longitudinal and circumferential axons studded with numerous varicose swellings. The density of CGRP fibers was particularly high at the bifurcation of major arteries. A few CGRP fibers cross the midline to innervate arteries on the contralateral side of the arterial tree. The arteries of the caudal circulation were sparsely innervated by CGRP fibers. In the trigeminal ganglion, about 30% of the ganglion cells had CGRP immunoreactivity. The cell size of most (75%) of CGRP neurons was less than 30 micron in diameter. There was no significant difference in staining density between small and large CGRP neurons. Unilateral transection of the maxillary and mandibular divisions of the trigeminal nerve caused a substantial decrease of CGRP immunoreactivity in the ipsilateral dorsal two-thirds of the trigeminal nucleus and cervical spinal cord but did not noticeably change the diameter of the vascular lumen or the densities of CGRP fibers in the walls of the cerebral arteries. In contrast, unilateral transection that included the ophthalmic division eliminated CGRP fibers on the ipsilateral cerebral arteries and eliminated CGRP immunoreactivity throughout the trigeminal nucleus in the brainstem and rostral cervical cord. In addition, these lesions caused a significant reduction in the diameter of the denervated arteries. The present study demonstrates that CGRP, a putative neurotransmitter/neuromodulator, is especially abundant in the rostral cerebral circulation and is derived from the ipsilateral ophthalmic division of the trigeminal nerve. In addition, the loss of CGRP perivascular nerves is associated with a reduction of the arterial lumen. This suggests that CGRP is a strong candidate as a nerve-derived trophic factor at trigeminal terminals and provides additional evidence that CGRP is a component in the trigeminovascular system influencing vascular diameter.     

The effect of sympathectomy on calcitonin gene-related peptide levels in the rat trigeminovascular system

The effect of sympathectomy on the calcitonin gene-related peptide (CGRP) level in the rat primary trigeminal sensory neurone was investigated. Six weeks after bilateral removal of the superior cervical ganglion there was a 70% rise in the CGRP content of the iris and the pial arteries, a 34% rise in the concentration in the trigeminal ganglion but no change in the brainstem. The CGRP rise in both end organs suggests that this phenomenon may be common to all peripheral organs receiving combined sensory and sympathetic innervations. The lack of any rise in the brainstem CGRP content raises the possibility that this process spares central terminations. In contrast, the level of neuropeptide Y, a peptide mainly contained in sympathetic terminals, fell to 35% of control values in the iris and pial arteries whilst the trigeminal ganglion and brainstem concentrations remained unchanged. The possible relevance of these observations to the clinical syndrome of postsympathectomy pain (sympathalgia) is discussed. There are similarities between the delayed onset of the human pain state and the delayed rise in sensory peptides after sympathectomy.     

Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution

Calcitonin gene-related peptide (CGRP) is a key mediator in primary headaches including migraine. Animal models of meningeal nociception demonstrate both peripheral and central CGRP effects; however, the target structures remain unclear. To study the distribution of CGRP receptors in the rat trigeminovascular system we used antibodies recognizing two components of the CGRP receptor, the calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 1 (RAMP1). In the cranial dura mater, CLR and RAMP1 immunoreactivity (-ir) was found within arterial blood vessels, mononuclear cells, and Schwann cells, but not sensory axons. In the trigeminal ganglion, besides Schwann and satellite cells, CLR- and RAMP1-ir was found in subpopulations of CGRP-ir neurons where colocalization of CGRP- and RAMP1-ir was very rare ( approximately 0.6%). CLR- and RAMP1-ir was present on central, but not peripheral, axons. In the spinal trigeminal nucleus, CLR- and RAMP1-ir was localized to "glomerular structures," partly colocalized with CGRP-ir. However, CLR- and RAMP1-ir was lacking in central glia and neuronal cell bodies. We conclude that CGRP receptors are associated with structural targets of known CGRP effects (vasodilation, mast cell degranulation) and targets of unknown function (Schwann cells). In the spinal trigeminal nucleus, CGRP receptors are probably located on neuronal processes, including primary afferent endings, suggesting involvement in presynaptic regulation of nociceptive transmission. Thus, in the trigeminovascular system CGRP receptor localization suggests multiple targets for CGRP in the pathogenesis of primary headaches.     

Origins and distribution of cerebrovascular nerve fibers showing calcitonin gene-related peptide-like immunoreactivity in the major cerebral artery of the dog

The origins and overall distribution of perivascular nerve fibers showing calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) in the major cerebral arteries were investigated immunohistochemically in the dog by using whole-mount preparations of the arterial trees around the circle of Willis. Perivascular nerve fibers with CGRP-LI were seen most abundantly in the basilar artery, vertebral artery, common anterior cerebral artery, proximal part of the anterior cerebral artery, and terminal part of the internal carotid artery. They were far less numerous in the middle cerebral artery, posterior cerebral artery, superior cerebellar artery, and distal part of the anterior cerebral artery. Neuronal cell bodies with CGRP-LI were observed in the trigeminal, nodose, superior cervical, and dorsal root ganglia. CGRP-LI fibers in the large pial arteries in the circle of Willis were eliminated ipsilaterally after unilateral transection of the ophthalmic division of the trigeminal nerve, and slightly reduced in number ipsilaterally after unilateral transection of the maxillary division of the trigeminal nerve. They did not show any noticeable changes after unilateral transection of the mandibular division of the trigeminal nerve. On the other hand, CGRP-LI fibers in the basilar and vertebral arteries did not show any appreciable changes after unilateral transection of the trigeminal nerve, but they were eliminated after bilateral ganglionectomy of the dorsal root ganglia of the first, second, and third cervical nerves. After ganglionectomy of the ciliary, pterygopalatine, otic, nodose, or superior cervical ganglion, no changes were observed in perivascular nerve fibers with CGRP-LI in the major cerebral arteries.(ABSTRACT TRUNCATED AT 250 WORDS)     

Local anesthetics inhibit veratridine-induced secretion of calcitonin gene-related peptide (CGRP) from cultured rat trigeminal ganglion cells

Secretion of calcitonin gene-related peptide (CGRP) was studied with the model system of dispersed adult rat trigeminal ganglion cells. Veratridine stimulated secretion of CGRP immunoreactivity. Tetrodotoxin and local anesthetics inhibited veratridine-stimulated peptide secretion. These observations implicate sodium channels in CGRP secretion and are consistent with a role for the peptide as an extracellular neuromodulator in the sensory nervous system.     

Distribution of calcitonin gene-related peptide immunoreactivity in relation to the rat central somatosensory projection

The distribution of the neuropeptide calcitonin gene-related peptide (CGRP) was studied in relation to the known subcortical somatosensory pathways and contiguous systems in the central nervous system (CNS) of rats by using peroxidase histochemical methods in order to relate zones of immunoreactivity (IR) to cytoarchitecture. CGRP is the most ubiquitous peptide found to date in sensory ganglion cells: principally small and medium-size neurons emitting thin axons inferred to be largely nociceptive in function on the basis of the peripheral distribution of their terminals. Its apparent absence in sympathetic axons provides an especially useful sensory marker. The distribution of CGRP-IR axons displays remarkable selectivity at each level of the CNS. The trigeminal root distributes axons primarily to the pericornual layers (laminae I and II) of spinal V nucleus caudalis and to subnucleus oralis, evading the subnucleus interpolaris and contributing only few axons to principal V. Although there are only a few CGRP-IR somata at each level, heavily labeled axon trajectories can be traced to the nuclei of the solitary tract, the parabrachial nuclei, several sectors of the caudal medial thalamus, and the central nucleus of the amygdala. A sector of labeled neuron somata lies contiguous to each of these axon terminal zones, the largest of which is a thalamic nucleus containing cells of distinctive dendritic architecture extending from the periaqueductal gray across the posterior group nuclei to the peripeduncular nucleus, forming a linear array at the mesodiencephalic junction. The relation of CGRP-IR axonal distribution to spinothalamic, visceral, and gustatory systems is discussed in the context of a specialized "chemosensory" component of the thin-fiber somatosensory system.     

Coexistence of calcitonin gene-related peptide and vasoactive intestinal peptide in cholinergic sympathetic innervation of rat sweat glands

Immunoreactivity for calcitonin gene-related peptide (CGRP) has been localized with indirect immunofluorescence techniques in the cholinergic sympathetic fibers that innervate eccrine sweat glands in the rat. This innervation also contains vasoactive intestinal peptide-like immunoreactivity (VIP-IR). A small proportion of principal neurons in stellate and lumbar sympathetic ganglia which provide innervation to the sweat glands contain detectable CGRP-immunoreactivity. The CGRP-IR neurons are immunoreactive for VIP; however, many VIP-IR neurons in these ganglia do not contain detectable levels of CGRP-IR.     

Glial cell line-derived neurotrophic factor increases calcitonin gene-related peptide immunoreactivity in sensory and motoneurons in vivo

Calcitonin gene-related peptide (CGRP) is expressed at high levels in roughly 50% of spinal sensory neurons and plays a role in peripheral vasodilation as well as nociceptive signalling in the spinal cord. Spinal motoneurons express low levels of CGRP; motoneuronal CGRP is thought to be involved in end-plate plasticity and to have trophic effects on target muscle cells. As both sensory and motoneurons express receptors for glial cell line-derived neurotrophic factor (GDNF) we sought to determine whether CGRP was regulated by GDNF. Rats were treated intrathecally for 1-3 weeks with recombinant human GDNF or nerve growth factor (NGF) (12 microg/day) and dorsal root ganglia and spinal cords were stained for CGRP. The GDNF treatment not only increased CGRP immunoreactivity in both sensory and motoneurons but also resulted in hypertrophy of both populations. By combined in situ hybridization and immunohistochemistry we found that, in the dorsal root ganglia, CGRP was up-regulated specifically in neurons expressing GDNF but not NGF receptors following GDNF treatment. Despite the increase in CGRP in GDNF-treated rats, there was no increase in thermal or mechanical pain sensitivity, while NGF-treated animals showed significant decreases in pain thresholds. In motoneurons, GDNF increased the overall intensity of CGRP immunoreactivity but did not increase the number of immunopositive cells. As GDNF has been shown to promote the regeneration of both sensory and motor axons, and as CGRP appears to be involved in motoneuronal plasticity, we reason that at least some of the regenerative effects of GDNF are mediated through CGRP up-regulation.     

Pituitary adenylate cyclase-activating polypeptide (PACAP) protects dorsal root ganglion neurons from death and induces calcitonin gene-related peptide (CGRP) immunoreactivity in vitro

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a recently discovered neuropeptide which is present both in the central and peripheral nervous system of adult rats. Here we show that PACAP is also expressed by dorsal root ganglion sensory neurons of embryonic and newborn rats. To characterize the effects of PACAP on dorsal root ganglion (DRG) neurons, dissociated cultures were established and incubated in the absence or presence of this neuropeptide. The results show that PACAP increases the survival of cultured DRG neurons, and the effect was comparable to that of nerve growth factor (NGF). In DRG explants, PACAP induces the immunoreactivity for the neuropeptide calcitonin gene-related peptide (CGRP). PACAP also promoted the outgrowth of neurites in the DRG cultures. The present results show that PACAP acts as a trophic factor for DRG neurons and that it is able to modulate the expression of another neuropeptide in the ganglia. The presence of PACAP in normal DRG and after nerve lesions suggests that PACAP acts in a autocrine/paracrine manner possibly in conjunction with other neurotrophic factors such as nerve growth factor. J. Neurosci. Res. 51:243-256, 1998. © 1998 Wiley-Liss, Inc.     

Central projection of calcitonin gene-related peptide (CGRP)- and substance P (SP)-immunoreactive trigeminal primary neurons in the rat

Substance P (SP) is implicated in transmission of primary afferent nociceptive signals. In primary neurons, SP is colocalized with calcitonin gene-related peptide (CGRP), which is another neuropeptide marker for small to medium primary neurons. CGRP coreleased with SP augments the postsynaptic effect of SP and thereby modulates the nociceptive transmission. This study demonstrates the distribution of CGRP-like immunoreactivity (-ir) and SP-ir in the lower brainstem of normal rats and after trigeminal rhizotomy or tractotomy at the level of subnucleus interpolaris (Vi). By comparing the results obtained from normal and deafferented rats, we analyzed the central projection of trigeminal primary nociceptors. The CGRP-immunoreactive (-ir) trigeminal primaries projected to the entire rostrocaudal extent of the spinal trigeminal nucleus, the principal nucleus (PrV), the paratrigeminal nucleus (paraV), and the lateral subnucleus of solitary tract nucleus (STN) on the ipsilateral side. The trigeminal primaries projecting to the spinal trigeminal nucleus, paraV and STN also contained SP-ir. The ipsilateral trigeminal primaries were the exclusive source of CGRP-ir terminals in the PrV, the Vi and the dorsomedial nucleus within the subnucleus oralis (Vo). The medullary dorsal horn (MDH) and the lateral edge of Vo received convergent CGRP-ir projection from the ipsilateral trigeminal primaries and other neurons. The glossopharyngeal and vagal primaries are candidates for the source of CGRP-ir projection to the Vo and the MDH, while the dorsal root axons supply the MDH with CGRP-ir terminals. In addition, contralateral primary neurons crossing the midline appear to contain CGRP and to terminate in the MDH. J. Comp. Neurol. 378:425–442, 1997. © 1997 Wiley-Liss, Inc.     

Sexually dimorphic expression of calcitonin gene-related peptide (CGRP) immunoreactivity by rat mediobasal hypothalamic neurons

Although the hypothalamic arcuate nucleus is a sexually dimorphic region of the rat brain, there are no reports of sex differences in the number of neurons containing specific neuropeptides within this structure. As cells synthesizing calcitonin gene-related peptide (CGRP) have been shown to exhibit sex differences in other steroid-receptive regions of the rat brain, we examined whether the CGRP-immunoreactive cells located in the mediobasal hypothalamus may also be sexually dimorphic. Immunostaining of sections from male and female colchicine-treated rats revealed a small population of CGRP-immunoreactive cells distributed throughout the arcuate nucleus. Immunoreactive cells were also detected in the lateral hypothalamic perifornical region, dorsomedial, posterior periventricular and ventral tuberomammillary nuclei, and zona incerta. Cell count analysis revealed approximately twice as many CGRP-immunoreactive cell profiles in the rostral (P < 0.01), middle (P < 0.001), and caudal (P < 0.01) thirds of the arcuate nucleus of male rats compared with females. A significant sex difference in immunoreactive cell numbers (male > female) was also detected within the caudal dorsomedial nucleus (P < 0.05) but not in the posterior periventricular nucleus, perifornical region and zona incerta. Although fibers immunoreactive for CGRP were identified in low density throughout the mediobasal hypothalamus, only female rats displayed prominent fiber staining in the periventricular region. Double-labelling immunofluorescence experiments revealed that the CGRP-immunoreactive cells within the zona incerta, but not the hypothalamus, were also immunoreactive for tyrosine hydroxylase; at least 60% of the A13 dopaminergic neurons co-express CGRP. These results provide evidence that sex differences exist in the number of specific neuropeptide-synthesizing cells within the hypothalamic arcuate nucleus and provide further examples of cell populations expressing CGRP immunoreactivity in a sexually dimorphic manner. © 1996 Wiley-Liss, Inc.     

Galanin immunoreactivity in autonomic innervation of the cat eye

In an immunohistochemical study, we find that galanin is much more widely distributed in the peripheral innervation of the cat eye than in other animals so far examined. Previous studies of rat and pig eyes have revealed sparse galanin-positive nerves that presumbably originate in the trigeminal ganglion. In contrast, the cat has a rich supply of galanin-containing nerve fibers throughout the uvea. Galanin-positive varicose nerves concentrate densely in iris muscles and distribute more sparsely in the ciliary muscle. The ciliary processes have a plexus of galanin-positive nerve underlying the ciliary epithelium at their base and positive nerve fibers coursing within their stroma. The ciliary artery and its branch vessels in the uvea are invested with a dense plexus of galanin-positive nerves. All autonomic ganglia supplying the eye contain cells that express galanin. It is present in 97% of superior cervical ganglion cells, coexisting with both tyrosine hydroxylase and neuropeptide Y; in 80% of pterygopalatine ganglion cells, most of whiclh also contain vasoactive intestinal peptide; and in approximately 25% of ciliary ganglion celis. After unilateral superior cervical ganglionectoiny, galanin-positive nerves almost totally disappear from the iris muscles, demonstrating that they are predominantly of sympathetic origin. Galanin-positive nerves investing the ciliary artery and choroidal blood vessels are not detectably reduced by sympathectomy, indicating that perivascular parasympathetic nerves from the pterygopalatine ganglion also express galanin. Other galanin-containing nerves in the eye can originate from the trigeminal and ciliary ganglia. The prominence of galanin in the ocular autonomic innervation of the cat provides an opportunity to explore the physiological effects of this neuropeptide in the eye. © 1994 Wiley-Liss, Inc.     

Effect of calcitonin gene-related peptide (CGRP) on avian appetite-related processes

Calcitonin gene-related peptide (CGRP) is released from the gastrointestinal tract following ingestion and causes satiety in mammals. Its effects on appetite in non-mammalian vertebrates are unreported. In Experiment 1, fasted chicks reduced food and water intake after central injection of CGRP. These effects were not associated with increased plasma corticosterone concentration. In Experiment 2, we showed that the effect on water intake was independent of food intake. In Experiment 3, central CGRP caused increased c-Fos immunoreactivity in the arcuate (ARC) nucleus, paraventricular nucleus (PVN), periventricular (PHN) and ventromedial (VMH) hypothalamic nuclei. The results of Experiment 4 demonstrate that intraperitoneal injection of CGRP also causes reduced food and water intake. c-Fos immunoreactivity was increased in the ARC, PHN, PVN and VMH in Experiment 5 after intraperitoneal injection of CGRP. Lastly in Experiment 6, we showed that central CGRP changes the type of pecks from feeding to exploratory, and reduces the number of escape attempts. The effect of CGRP appears to be primary on appetite in chicks. In conclusion, the mechanisms of CGRP induced satiety have some similarities and differences between avian and rodent models. The results presented here provide new insight into the evolution of vertebrate satiety regulatory mechanisms.     

The myotropic and plasma-calcium modulating effects of calcitonin gene-related peptide (CGRP)

Human and rat calcitonin gene-related peptides cause a dose-related contraction of guinea pig ileum, which is antagonised by an anti-histamine, mepyramine, and an anticholinergic compound, hyoscine. Both peptides also cause a positive inotropic and a positive chronotropic effect in the rat isolated auricle and these responses are antagonised by propranolol, a B adrenoceptor blocker. Further, the peptides lower plasma calcium levels in both rats and rabbits in a dose-related manner resembling calcitonin; in the rabbit, but not in the rat, the initial calcium lowering effect is succeeded by hypercalcaemia at higher doses, while in the chick, only the parathyroid hormone-like calcium-raising effect is seen.     

Human brain calcitonin gene-related peptide (CGRP) is concentrated in the locus caeruleus

A quantitative survey of calcitonin gene-related peptide (CGRP) in brain, peripheral nerve and cerebrospinal fluid (CSF) was performed using radioimmunoassay (RIA) with antiserum against synthetic hCGRP. High levels (approximately 2000-15,000 fmol/mg protein) were found in the dorsal spinal cord, dorsal nerve and trigeminal nerve. Relatively large amounts (500-2000) were found in parts of the hypothalamic-pituitary axis, peripheral nerve and, for the first time, in the locus caeruleus. Low levels of CGRP (less than 500) were detected in the cerebrum, subcortical nuclei and cerebellum. CGRP, not previously reported in CSF, was detectable in all of 27 CSF specimens with mean values of 30 +/- 4.5 pmol/L (SE). Simultaneous plasma CGRP levels were higher and, when elevated by antihypertensive treatment were not increased in CSF, just as astronomical plasma levels of calcitonin in medullary carcinoma of the thyroid are not reflected in CSF. Our data confirm and extend the results of previous human and animal studies with evidence of species variation: humans have low CGRP levels in subcortical nuclei whereas high levels have been found in rat caudate-putamen and amygdala. The high level of CGRP in the locus caeruleus, the major source of noradrenergic neurotransmission in the CNS, is in harmony with the presumed functions of the LC and the very potent hemodynamic activity of CGRP.     

Presence of calcitonin gene-related peptide (CGRP) and substance P (SP) immunoreactivity in intraepidermal free nerve endings of cat skin

Dorsal roots are absent from the tails of Xenopus larvae. Sensory afferents instead enter the spinal cord via the ventral roots. After reaching the cord these axons travel diagonally within the lateral fasciculus of the cord to reach the dorsolateral fiber bundle in which they ascend to the hindbrain. Sensory afferents entering together in the same ventral root make this traverse individually rather than as a group, but coalesce again at the ascending tract.     

Appearance and distribution of neurofilament immunoreactivity in iris nerves

We have used antiserum raised against neurofilament (NF) protein and indirect immunofluorescence techniques to visualize neuronal structures in rodent, cat, and cow irides. In the adult rat iris a large population of nerve fibers with a nonautonomic distribution show NF-like immunoreactivity. In whole mounts, smooth fluorescent fibers were seen in a fine-meshed plexus from the sphincter margin to the ciliary processes. Superimposed, a sparse pattern of thick meandering axon bundles were seen. Electroblotting and peroxidase immunochemical staining techniques unequivocally showed the presence of all three NF polypeptides in the adult rat iris. Adult mouse irides showed a somewhat sparser pattern of NF-positive nerves than that of the rat. Adult guinea pig irides contained irregular NF-positive fibers and few axon bundles. In cryostat-sectioned cat iris numerous irregularly distributed individual fibers were found, whereas in similarly sectioned cow iris thick NF-positive axon bundles were more numerous. By embryonic day 18 numerous sparse NF-positive axons were seen, and the subsequent gradual increase in both axons in bundles and fine-meshed plexuses of individual fibers produced an appearance similar to that in the adult by 6 days of postnatal age. One week after grafting of irides to the anterior eye chamber, most NF-positive nerves had disappeared from the iris grafts. Sympathetic and parasympathetic denervation of the irides did not influence the distribution of the NF-positive iris nerves. Five days after electrothermal lesion of the trigeminal nerve just distal to its ganglion a large proportion of the NF-positive nerves had disappeared from the iris. All perikarya in the parasympathetic ciliary and most perikarya in the superior cervical sympathetic and in the trigeminal sensory ganglion showed NF immunoreactivity. The present report shows a way to visualize nonautonomic nerve populations in stretch-prepared as well as sectioned irides by immunofluorescence techniques using an antiserum to neurofilament protein.     

Distribution of gastrin‐releasing peptide in the rat trigeminal and spinal somatosensory systems

Gastrin‐releasing peptide (GRP) has recently been identified as an itch‐specific neuropeptide in the spinal sensory system in mice, but there are no reports of the expression and distribution of GRP in the trigeminal sensory system in mammals. We characterized and compared GRP‐immunoreactive (ir) neurons in the trigeminal ganglion (TG) with those in the rat spinal dorsal root ganglion (DRG). GRP immunoreactivity was expressed in 12% of TG and 6% of DRG neurons and was restricted to the small‐ and medium‐sized type cells. In both the TG and DRG, many GRP‐ir neurons also expressed substance P and calcitonin gene‐related peptide, but not isolectin B₄. The different proportions of GRP and transient receptor potential vanilloid 1 double‐positive neurons in the TG and DRG imply that itch sensations via the TG and DRG pathways are transmitted through distinct mechanisms. The distribution of the axon terminals of GRP‐ir primary afferents and their synaptic connectivity with the rat trigeminal sensory nuclei and spinal dorsal horn were investigated by using light and electron microscopic histochemistry. Although GRP‐ir fibers were rarely observed in the trigeminal sensory nucleus principalis, oralis, and interpolaris, they were predominant in the superficial layers of the trigeminal sensory nucleus caudalis (Vc), similar to the spinal dorsal horn. Ultrastructural analysis revealed that GRP‐ir terminals contained clear microvesicles and large dense‐cored vesicles, and formed asymmetric synaptic contacts with a few dendrites in the Vc and spinal dorsal horn. These results suggest that GRP‐dependent orofacial and spinal pruriceptive inputs are processed mainly in the superficial laminae of the Vc and spinal dorsal horn. J. Comp. Neurol. 522:1858–1873, 2014. © 2013 Wiley Periodicals, Inc.     

Changes in calcitonin gene-related peptide (CGRP)-containing vasodilator nerve activity in hypertension

The role of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves in maintenance of hypertension was investigated in the perfused mesenteric vascular beds isolated from spontaneously hypertensive rats (SHR), deoxycorticosterone-salt-induced hypertensive rats (DOCA-Salt-HR) and corresponding normotensive control rats (Wistar Kyoto rats, WKY and Wistar rats, NR). In the mesenteric artery with an active tone, the neurogenic vasodilation induced by perivascular nerve stimulation (PNS, 0.5-8 Hz), which was mediated by CGRP nerves, was markedly decreased in adult SHR (15-week-old) when compared with age-matched WKY, whereas the vasodilation in DOCA-Salt-HR was similar in magnitude to that in NR. The vasodilator response to exogenously applied CGRP was greater in SHR than in WKY, whereas no difference was found between DOCA-Salt-HR and NR. The neurogenic release of CGRP-like immunoreactivity (CGRP-LI) induced by PNS of the mesenteric artery was significantly decreased in SHR compared to that of WKY. In addition, immunohistochemical studies showed decreased populations of CGRP-LI fibers in the mesenteric artery of SHR compared to those in WKY. These results suggest that CGRP-containing vasodilator innervation is greatly decreased in SHR with established hypertension. It is also suggested that the decreased vasodilator mechanism by CGRP-containing nerves contributes to the maintenance of hypertension.