Involvement of substance P present in primary afferent neurones in modulation of cutaneous blood flow in the instep of rat hind paw

Yonehara, Norifumi; Chen, Jiqiang; Imai, Yasuo; Inoki, Reizo

doi:10.1111/j.1476-5381.1992.tb14325.x

Cited by 21 publications

(8 citation statements)

References 42 publications

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“…Indeed, those researchers reported no change in peripheral vascular tone and blood pressure after administration of NK-1r antagonists, although exogenous SP caused vasodilatation in the forearm skin through the activation of endothelial NK-1r. With respect to rat skin microcirculation, SP appears to exert tonic regulation of the vascular tone (Yonehara et al, 1992(Yonehara et al, , 1993. This suggests that blood flow is regulated differentially in rat and human.…”

Section: Sp and Vascular Blood Flowmentioning

confidence: 96%

Light and electron microscopic study of the distribution of substance P‐immunoreactive fibers and neurokinin‐1 receptors in the skin of the rat lower lip

Ruocco

Cuello

Shigemoto

et al. 2001

J of Comparative Neurology

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Cutaneous antidromic vasodilatation and plasma extravasation, two phenomena that occur in neurogenic inflammation, are partially blocked by substance P (SP) receptor antagonists and are known to be mediated in part by mast cell-released substances, such as histamine, serotonin, and nitric oxide. In an attempt to provide a morphological substrate for the above phenomena, we applied light and electron microscopic immunocytochemistry to investigate the pattern of SP innervation of blood vessels and its relationship to mast cells in the skin of the rat lower lip. Furthermore, we examined the distribution of SP (neurokinin-1) receptors and their relationship to SP-immunoreactive (IR) fibers. Our results confirmed that SP-IR fibers are found in cutaneous nerves and that terminal branches are observed around blood vessels and penetrating the epidermis. SP-IR fibers also innervated hair follicles and sebaceous glands. At the ultrastructural level, SP-IR varicosities were observed adjacent to arterioles, capillaries, venules, and mast cells. The varicosities possessed both dense core vesicles and agranular synaptic vesicles. We quantified the distance between SP-IR varicosities and blood vessel endothelial cells. SP-IR terminals were located within 0.23-5.99 microm from the endothelial cell layer in 82.7% of arterioles, in 90.2% of capillaries, and in 86.9% of venules. Although there was a trend for SP-IR fibers to be located closer to the endothelium of venules, this difference was not significant. Neurokinin-1 receptor (NK-1r) immunoreactivity was most abundant in the upper dermis and was associated with the wall of blood vessels. NK-1r were located in equal amounts on the walls of arterioles, capillaries, and venules that were innervated by SP-IR fibers. The present results favor the concept of a participation of SP in cutaneous neurogenic vasodilatation and plasma extravasation both by an action on blood vessels after binding to the NK-1r and by causing the release of substances from mast cells after diffusion through the connective tissue.

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Section: Sp and Vascular Blood Flowmentioning

confidence: 96%

Light and electron microscopic study of the distribution of substance P‐immunoreactive fibers and neurokinin‐1 receptors in the skin of the rat lower lip

Ruocco

Cuello

Shigemoto

et al. 2001

J of Comparative Neurology

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“…Activation of the terminal results in a uniform reaction of vasodilatation and plasma extravasation that is commonly referred to as neurogenic inflammation. This is maintained by the release of neuropeptides, e.g., CGRP, from the nerve terminals of unmyelinated afferents during activation (Yonehara et al, 1992;Kilo et al, 1997;Kress et al, 1999). Recently, we have demonstrated CGRP release from rat skin in vitro induced by noxious heat (Kessler et al, 1999).…”

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confidence: 98%

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

2000

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Proinflammatory cytokines contribute to the development of inflammatory and neuropathic pain and hyperalgesia in many in vivo models. The rat skin model was used to investigate the effects of proinflammatory cytokines on the basal and heatevoked release of calcitonin gene-related peptide from nociceptors in vitro. In contrast to the excitatory effects of cytokines observed in vivo, none of the cytokines tested evoked any calcitonin gene-related peptide (CGRP) release at normal skin temperature of 32°C. However, the cytokines IL-1␤, tumor necrosis factor (TNF)-␣, and IL-6 but not IL-8 induced a pronounced and transient sensitization of the heat-evoked CGRP release from nociceptors in vitro. This heat sensitization was dose dependent, with EC 50 for IL-1␤ of 2.7 ng/ml and for TNF-␣ of 3.1 ng/ml. The maximum IL-1␤ effect reached almost 600% of the heat-evoked release, and the maximum TNF-␣ effect induced a rise in CGRP release of 350%. In contrast to IL-1␤ and TNF-␣, IL-6 did not induce heat sensitization when applied alone but was only effective in the presence of soluble IL-6 receptor. This suggests a constitutive expression of signaling receptors for TNF and IL-1␤ and the signal transduction molecule gp130 but not IL-6 receptor or IL-8 receptor. Furthermore, the acute cytokine signaling observed in the present study was independent of transcriptional pathways because sensitization occurred on short latency in vitro and under conditions that excluded chemotactic accumulation of immune cells from blood vessels. Our results demonstrate that interleukins may play an important role in the initiation of heat hyperalgesia in inflammation and neuropathy.

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“…Moreover, it is known that treatment of newborn rats with capsaicin results in selective and permanent degeneration of small diameter afferent fibers with significant decrease in the content of SP (15). We have reported that pretreatment of newborn rats with capsaicin inhibited both phases of the biphasic flow response evoked by antidromic stimula tion of the sectioned sciatic nerve (7). From these find ings, it seems likely that stimulation-induced changes in CBF are mediated by SP released from the peripheral end ings of capsaicin sensitive small-diameter afferent fibers present in the sciatic nerve.…”

Section: Discussionmentioning

confidence: 89%

Effect of Morphine on Changes in Cutaneous Blood Flow Induced by Antidromic Stimulation of Primary Afferent Fibers in the Hind Instep of Rats

Yonehara

Tang

Inoki

1993

Japanese Journal of Pharmacology

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ABSTRACT-The effects of morphine on the release of immunoreactive substance P (iSP) into the sub cutaneous perfusate and the changes in cutaneous blood flow (CBF) elicited by antidromic stimulation of sectioned sciatic nerve were investigated in the instep of the hind paw of rats. Antidromic stimulation of the sectioned sciatic nerve induced a marked increase in iSP release into the subcutaneous perfusate and a biphasic flow response consisting of an initial transient decrease followed by an increase. Both the iSP re lease and the increase of the CBF evoked by antidromic stimulation (the second phase) were significantly in hibited by intra-arterial (i.a.) infusion of morphine (30 ttmol/kg). These inhibitory effects of morphine were antagonized by pretreatment with naloxone (2 mg/kg, i.p.). The i.a. infusion of SP (0.25 pmol/kg) induced a biphasic flow response similar to that elicited by antidromic stimulation of the sectioned sciatic nerve. Neither phase induced by i.a. infusion of SP was affected by preinfusion of morphine (10 or 30 pmol/kg, i.a.). We suggest that morphine applied locally mainly acts on the peripheral endings of small-diameter afferent fibers, not on blood vessels, and that activation of this site is involved in the regulation of the microcirculatory hemodynamics of cutaneous tissue through inhibition of SP release. Keywords:Substance P, Cutaneous blood flow, Antidromic stimulation, Morphine, NaloxoneSmall-diameter primary afferent neurons are known to transmit nociceptive messages to central neurons (1) and also to be important in the inflammatory process in the periphery through axon-reflex mechanisms (2). In fact, vasodilatation, swelling and pain, which are the principal signs of inflammation, can all be produced by the activa tion of small-diameter primary afferent neurons (3). Sev eral lines of evidence indicate that substances released from capsaicin-sensitive, small-diameter primary afferent neu rons mediate these signs of inflammation (4). There is some evidence indicating that substance P (SP) may be one of the predominant mediators responsible for the ini tiation of neurogenic inflammatory responses. For exam ple, electrical stimulation of small-diameter afferent fibers was shown to induce the release of SP in the periphery (5 7) and to produce the same cutaneous vasodilatation and plasma extravasation as that induced by intradermal or intra-arterial administration of SP (8). These findings suggest that afferent impulses from nerve terminals of small-diameter afferent fibers generated by noxious stimu li may cause the release of SP, which may finally control the inflammatory response through regulation of the microcirculation.Opioids, which are known to inhibit the release of SP from the central terminals of small-diameter afferent fibers (9, 10), have been also shown to inhibit stimulus evoked SP release into the subcutaneous space (11) and neurogenic inflammation (12, 13).The aim of this study was to elucidate the site of action of opioids in peripheral sensory nerves-cutaneous bl...

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Involvement of substance P present in primary afferent neurones in modulation of cutaneous blood flow in the instep of rat hind paw

Cited by 21 publications

References 42 publications

Light and electron microscopic study of the distribution of substance P‐immunoreactive fibers and neurokinin‐1 receptors in the skin of the rat lower lip

Light and electron microscopic study of the distribution of substance P‐immunoreactive fibers and neurokinin‐1 receptors in the skin of the rat lower lip

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

Effect of Morphine on Changes in Cutaneous Blood Flow Induced by Antidromic Stimulation of Primary Afferent Fibers in the Hind Instep of Rats

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