Biomedical subjects

Susan D Brain

Publications and source records attributed to Susan D Brain.

At least 19 recordsLinked to original sources

PubMed2006

Neutrophils-derived peroxynitrite contributes to acute hyperalgesia and cell influx in zymosan arthritis.

We investigated the contribution of neutrophils to joint hyperalgesia and peroxynitrite formation in zymosan arthritis. Rats received 1 mg zymosan intra-articular, and joint hyperalgesia was measured using the rat knee-joint articular incapacitation test. After 6 h, joint exudates were collected by aspiration for the assessment of cell influx, myeloperoxidase activity, and nitrite (as an index of nitric oxide formation) levels. Nitrotyrosine content, used as an index of peroxynitrite formation, was measured in joint exudates, using enzyme-linked immunosorbent assay. A group of rats was rendered neutropenic through the administration of a rabbit anti-rat neutrophil antibody (2 ml kg(-1), i.p.) 30 min before injection of 1 mg zymosan intra-articular. Other groups received uric acid (100 or 250 mg kg(-1), i.p.), the peroxynitrite scavenger, 30 min before 1 mg zymosan intra-articular. Controls received the vehicle. The significant inhibition of joint hyperalgesia in neutropenic animals was associated to significantly decreased cell influx, myeloperoxidase activity, nitric oxide, and nitrotyrosine levels in the joint exudates, as compared to naive rats. Uric acid administration inhibited both hyperalgesia and cell influx, as compared to controls. Neutrophils are involved in both nitric oxide and peroxynitrite formation in zymosan arthritis, thereby contributing to acute joint hyperalgesia. Scavenging of reactive nitrogen species (e.g. peroxynitrite) inhibits neutrophil migration and joint hyperalgesia in the acute phase of zymosan arthritis in rats.

Acute Disease↗

PubMed2006

Galanin-like peptides exert potent vasoactive functions in vivo.

The cutaneous vasculature plays a key role in the pathophysiology of inflammatory skin diseases. The vascular activity is under the control of the peripheral nervous system that includes locally released neuropeptides. Recently, we detected receptors for the neuropeptide galanin in association with dermal blood vessels, suggesting a role of the galanin-peptide-family in the regulation of the cutaneous microvasculature. Therefore, we have investigated galanin and galanin-like peptide (GALP), a neuropeptide previously only considered to be involved in metabolism and reproduction in the central nervous system, for vaso-modulatory activity in the murine skin in vivo. Picomole amounts of intradermally injected galanin and GALP decreased cutaneous blood flow and inhibited inflammatory edema formation. Both the full-length GALP (1-60) and the putative smaller proteolytic fragment GALP (3-32) showed similar effects. These activities are most likely mediated by galanin receptors galanin receptor subtype 2 (GalR2) and/or galanin receptor subtype 3 (GalR3), because reverse transcription-PCR analysis of murine skin revealed messenger RNA (mRNA) expression of GalR2 and GalR3 but not of galanin receptor subtype 1. The lack of galanin receptor mRNAs in endothelial and smooth muscle cells indicates a neuronal localization of these receptors around the vessels. These results indicate functional activity of GALP in the periphery in vivo and suggest a potential role as an inflammatory modulator.

Animals↗

PubMed2006

How important are NK1 receptors for influencing microvascular inflammation and itch in the skin? Studies using Phoneutria nigriventer venom.

Pain and itch sensations are induced by depolarization of C-fibre nerves and possibly other types of fibres. We have evidence from several species, including mice, that skin plasma extravasation induced by the Phoneutria nigriventer spider venom (PNV) is dependent on tachykinin NK(1) receptors. We have now investigated the itching measured as bouts of scratching in response to intradermal (i.d.) PNV in wildtype (NK(1)(+/+)) and NK(1) receptor knockout (NK(1)(-/-)) mice. Mice, either NK(1)(+/+) or NK(1)(-/-), were given a single i.d. injection (0.05 ml) of test agent or vehicle into the shaved dorsal skin, in the intercostal region, in a randomized way. The bouts of scratching were recorded in a blinded manner for 60 min. Oedema formation was concomitantly assessed by the extravascular accumulation of i.v. injected (125)I-albumin. The i.d. injection of either substance P (at a high dose of 100 nmol/site), or PNV (0.3-10 microg/site) induced oedema formation in NK(1)(+/+) but substantially less was observed in NK(1)(-/-) mice, as previously reported. PNV also induced scratching, but significantly less scratching was observed in NK(1)(-/-) compared with NK(1)(+/+) mice. In contrast, SP did not induce significant scratching at amounts up to 100 nmol in NK(1)(+/+) mice. Experiments with an NK(1) receptor antagonist SR140333 (at doses that blocked PNV-induced oedema) revealed that whilst a local co-injection i.d. (1 nmol) in NK(1)(+/+) mice had no effect on PNV (3 microg/site)-induced scratching (18.5+/-3.7 vs. 14.4+/-3.5 bouts, mean+/-S.E.M., n=5-7), systemic treatment with SR140333 (120 nmol/kg, i.v.) significantly inhibited scratching (14+/-3.5 vs. 3.1+/-1.2 bouts, n=4-6; P<0.05). These results indicate that NK(1) receptors are involved in mediating PNV-induced scratching and that the location of the receptors is unlikely to be skin. Thus, a distinct separation between endogenous microvascular and PNV nociceptive NK(1)-dependent effects is suggested.

Administration, Topical↗

PubMed2006

Neuropeptides and their receptors: innovative science providing novel therapeutic targets.

This review examines our current understanding of the roles of some of the best known neuropeptides that have played major roles in our combined research programmes. Evidence obtained from over 75 years of research shows involvement of these transmitters in a wide range of organs relevant to cardiovascular, respiratory, cutaneous, neuronal and intestinal systems. There is an increasing understanding of the mechanisms involved in the release of the peptides (substance P and calcitonin gene-related peptide (CGRP)) from sensory nerves or, neuropeptide Y (NPY) from sympathetic, parasympathetic and nonadrenergic, noncholinergic (NANC) neurons. Responses in target tissues result from interactions of the neuropeptides, or related forms, with specific G-protein coupled receptors (GPCRs or 7 transmembrane-spanning, 7TM proteins) that belong to either rhodopsin-like, class 1 (neurokinin (NK) and NPY Y receptors) or secretin-like, class 2 GPCRs (CGRP receptors). The majority of receptors activated by our chosen neuropeptides are now cloned, with knowledge of preferred agonists and selective antagonists for many receptor subtypes within these families. The study of neuropeptides in animal models has additionally revealed physiological and pathophysiological roles that in turn have led to the ongoing development of new drugs, through utilization predominantly of antagonist activities.

Animals↗

PubMed2005

Pivotal role of endogenous tachykinins and the NK1 receptor in mediating leukocyte accumulation, in the absence of oedema formation, in response to TNFalpha in the cutaneous microvasculature.

Tachykinins including substance P (SP) are well known to play a role in influencing oedema formation and leukocyte accumulation during tissue insult and inflammation. Cutaneous inflammatory models to characterize a TNFalpha-dependent mechanism where endogenous SP act via the NK1 receptor to promote leukocyte accumulation in the absence of oedema formation were used. We found that TNFalpha induced dose-dependent leukocyte accumulation at 4 h, which returned towards basal levels at 8 h in NK1+/+ mice. This response was absent in both the NK1+/+ mice treated with an NK1 receptor antagonist and NK1-/- mice. At the highest dose IL-6 induced a significant accumulation in NK1+/+ and NK1-/- mice but IL-12 was ineffective. SP induced skin oedema but none of the cytokines did. Either co-injection of SP with low dose of TNFalpha (0.3 pmol/site) or SP previously injected (30 min) to TNFalpha evoked a significant increase in MPO activity when compared with that induced by the cytokine alone. In contrast, SP injected i.d. 3.5 h after TNFalpha failed to produce additive response. Control, but not capsaicin-pretreated rats (to deplete sensory nerves), exhibited a marked increase in MPO activity in response to TNFalpha. Histological analysis showed that TNFalpha caused tissue infiltrate of leukocytes in NK1+/+ mice, whilst leukocytes accumulated at intravascular sites in NK1-/- mice, but did not appear to emigrate, suggesting a defect in trans-endothelial migration. Interestingly, monocytes in addition to neutrophils accumulated 4 h post TNFalpha injection. In conclusion, the NK1 receptor plays a functional role in mediating leukocyte accumulation independently of the historically important NK1 mediated oedema formation. It seems that TNFalpha directly activates sensory nerve in addition to its chemoattractant activity. The NK1 receptor agonist influences the accumulation of monocytes in addition to that of PMN by 4 h, thus revealing an important influence of the NK1 receptor on TNFalpha mediated events in mouse skin.

Albumins↗

PubMed2005

Evidence for a novel protective role of the vanilloid TRPV1 receptor in a cutaneous contact allergic dermatitis model.

The purpose of this study was to examine the involvement of the transient receptor potential vanilloid receptor 1 (TRPV1) in inflammatory processes observed in murine allergic contact dermatitis (ACD). Oxazolone-induced ACD evoked a significant ear swelling after 24-72 h. It was augmented in TRPV1 knockout mice at all time points and supported by histological analysis and measure of TNF-alpha. However, tissue swelling and cytokine generation was significantly reduced in both neurokinin 1 receptor and calcitonin gene-related peptide (CGRP) knockout mice. A protective involvement of the TRPV1 receptor was identified of contact dermatitis distinct from mechanisms involving the major pro-inflammatory neuropeptides.

Adjuvants, Immunologic↗

PubMed2005

An examination of neurogenic mechanisms involved in mustard oil-induced inflammation in the mouse.

The mechanisms by which topical mustard oil causes vasodilatation in the mouse were investigated using the tachykinin NK1 receptor antagonist SR140333 and the calcitonin gene-related peptide (CGRP) antagonist BIBN4096BS, alongside alphaCGRP or NK1 receptor knockout mice. Blood flow was assessed by laser Doppler flowmetry and plasma extravasation by 125I-albumin accumulation. Mustard oil produced significant plasma extravasation and vasodilatation in wild type mice, although the plasma extravasation was less than that seen with capsaicin whilst the vasodilatation was greater. The plasma extravasation was abolished in tachykinin NK1 knockout mice, whilst the vasodilatation was enhanced. BIBN4096BS was unable to inhibit the vasodilatation in wild type mice but abolished it in the NK1 knockout mice. In alphaCGRP knockout mice, mustard oil also caused plasma extravasation and vasodilatation, which were both inhibited by treatment with SR140333. These data suggest that both a tachykinin NK1 receptor agonist and a CGRP agonist are active as vasodilators, producing redundancy, requiring blockade of both mediators to prevent vasodilatation.

Animals↗

PubMed2005

Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation.

OBJECTIVE: To investigate the endogenous involvement of transient receptor potential vanilloid 1 (TRPV1) in a model of knee joint inflammation in the mouse. METHODS: Following characterization of wild-type (WT) and TRPV1-knockout mice, inflammation was induced via intraarticular (IA) injection of Freund's complete adjuvant (CFA). Knee swelling was assessed as diameter, and inflammatory heat hyperalgesia was determined using the Hargreaves technique, for up to 3 weeks. At 18 hours, acute hyperpermeability was measured with 125I-albumin, and cytokines and myeloperoxidase activity, a marker of neutrophils, were assayed in synovial fluid extracts. The possibility that exogenous tumor necrosis factor alpha (TNFalpha) was involved in influencing TRPV1 activation was investigated in separate experiments. RESULTS: Increased levels of knee swelling, hyperpermeability, leukocyte accumulation, and TNFalpha were found in WT mice 18 hours after IA CFA treatment compared with saline treatment. Significantly less knee swelling and hyperpermeability were found in TRPV1-/- mice, but leukocyte accumulation and TNFalpha levels were similar in WT and TRPV1-/- mice. Knee swelling in response to CFA remained significantly higher for a longer period in WT mice compared with TRPV1-/- mice, with thermal hyperalgesic sensitivity observed at 24 hours and at 1 week in WT, but not TRPV1-/-, mice. Knee swelling was attenuated (P < 0.05) in TRPV1-/- compared with WT mice 4 hours after IA administration of TNFalpha. CONCLUSION: Our findings indicate that TRPV1 has a role in acute and chronic inflammation in the mouse knee joint. Thus, selective antagonism of TRPV1 should be considered as a potential target for treatment of acute and chronic joint inflammation.

Acute Disease↗

PubMed2004

Calcitonin gene-related peptide (CGRP) antagonists: blockers of neuronal transmission in migraine.

The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator that is contained in and released from sensory nerves. CGRP has been implicated in migraine, and the nonpeptide CGRP antagonist BIBN4096BS has been shown to be effective in clinical trials in migraine. To date, it has been largely assumed that the CGRP antagonist is effective due to its ability to block vasodilator activity. Goadsby and co-workers present data that now suggest that CGRP antagonists may also block neuronal transmission in migraine.

Animals↗

PubMed2004

Tachykinins regulate the function of platelets.

Evidence has been mounting for peripheral functions for tachykinins, a family of neuropeptides including substance P (SP), neurokinin A, and neurokinin B, which are recognized for their roles in the central and peripheral nervous system. The recent discovery of 4 new members of this family, the endokinins (EKA, B, C, and D), which are distributed peripherally, adds support to the notion that tachykinins have physiologic/endocrine roles in the periphery. In the present study we report a fundamental new function for tachykinins in the regulation of platelet function. We show that SP stimulates platelet aggregation, and underlying this is the intracellular mobilization of calcium and degranulation. We demonstrate the presence of the tachykinin receptors NK1 and NK3 in platelets and present evidence for the involvement of NK1 in SP-mediated platelet aggregation. Platelets were found to contain SP-like immunoreactivity that is secreted upon activation implicating SP-like substances in the autocrine/paracrine regulation of these cells. Indeed, NK1-blocking antibodies inhibited aggregation in response to other agonists. Of particular note is the observation that EKA/B cross-react in the SP immunoassay and are also able to stimulate platelet activation. Together our data implicate tachykinins, specifically SP and EKA/B, in the regulation of platelet function.

Blood Platelets↗

PubMed2004

Stress-induced suppression of the gonadotropin-releasing hormone pulse generator in the female rat: a novel neural action for calcitonin gene-related peptide.

In addition to its role as a potent vasodilator, calcitonin gene-related peptide (CGRP) is centrally involved in a variety of stress responses, including activation of the hypothalamo-pituitary-adrenocortical axis. It is well known that stress suppresses the activity of the hypothalamic GnRH pulse generator, the central regulator of LH and FSH pulses, resulting in reproductive dysfunction. The aim of this study was to test the hypothesis that CGRP has a critical role in mediating stress-induced suppression of pulsatile LH secretion in the rat. Ovariectomized rats were implanted with intracerebroventricular and iv cannulae. Central administration of CGRP (75 pmol-1.2 nmol) into the lateral cerebral ventricle resulted in a profound, dose-dependent suppression of LH pulses, which was reversed by a CGRP receptor antagonist (CGRP(8-37),1 nmol). Although the site of action of CGRP remains to be established, the induction of c-Fos expression in the preoptic area and hypothalamic paraventricular nucleus might suggest an involvement of these brain regions. Intravenous administration of CGRP did not affect LH pulses. Coadministration (intracerebroventricular) of CGRP (400 pmol) with a CRH antagonist (alpha-helical CRF(9-41), 26 nmol) partly blocked the CGRP-induced suppression of LH pulses. Furthermore, CGRP(8-37) (1 nmol) completely blocked hypoglycemic stress-induced suppression of LH pulses. These results suggest that the suppression of pulsatile LH secretion by central administration of CGRP may be mediated in part by CRH, and that CGRP may play a pivotal role in the normal physiological response of stress-induced suppression of the hypothalamic GnRH pulse generator, and hence the reproductive system.

Animals↗

PubMed2004

Vascular actions of calcitonin gene-related peptide and adrenomedullin.

This review summarizes the receptor-mediated vascular activities of calcitonin gene-related peptide (CGRP) and the structurally related peptide adrenomedullin (AM). CGRP is a 37-amino acid neuropeptide, primarily released from sensory nerves, whilst AM is produced by stimulated vascular cells, and amylin is secreted from the pancreas. They share vasodilator activity, albeit to varying extents depending on species and tissue. In particular, CGRP has potent activity in the cerebral circulation, which is possibly relevant to the pathology of migraine, whilst vascular sources of AM contribute to dysfunction in cardiovascular disease. Both peptides exhibit potent activity in microvascular beds. All three peptides can act on a family of CGRP receptors that consist of calcitonin receptor-like receptor (CL) linked to one of three receptor activity-modifying proteins (RAMPs) that are essential for functional activity. The association of CL with RAMP1 produces a CGRP receptor, with RAMP2 an AM receptor and with RAMP3 a CGRP/AM receptor. Evidence for the selective activity of the first nonpeptide CGRP antagonist BIBN4096BS for the CGRP receptor is presented. The cardiovascular activity of these peptides in a range of species and in human clinical conditions is detailed, and potential therapeutic applications based on use of antagonists and gene targeting of agonists are discussed.

Adrenomedullin↗

PubMed2004

The assessment of vasoactive properties of CGRP and adrenomedullin in the microvasculature: a study using in vivo and in vitro assays in the mouse.

The potent neuropeptide vasodilator, calcitonin gene-related peptide (CGRP), and the vasoactive peptide adrenomedullin (AM) are structurally related. Evidence from our laboratory has demonstrated that these peptides have potent microvascular actions of relevance to cardiovascular and inflammatory effects in health and disease. We wish to further investigate the actions of these peptides through studies in genetically modified mice. We have developed techniques to enable the quantitative analysis of CGRP and AM responses in the mouse microvasculature. A mouse isolated mesentery system was developed that measures changes in perfusion pressure used as an index of microvascular relaxation in the precontracted mesenteric microvascular bed. Bolus injections of CGRP and AM caused dose-dependent decreases in perfusion pressure that were proportional to vascular relaxation. An in vivo mouse skin assay was also used in which agents were injected intradermally into the dorsal skin. The effects of these agents was assessed by the extravascular accumulation of intravenously injected 125I-albumin for their ability to potentiate plasma extravasation induced by a mediator of increased microvascular permeability. CGRP and AM are not directly active in this assay, because it does not directly measure blood flow. However, the vasodilators acted in a potent and dose-dependent manner to significantly potentiate edema formation. The results demonstrate the potent activity of CGRP and the activity (although 100- to 300-fold less potent) of AM. Furthermore, the results demonstrate the increased potency of CGRP in the microvasculature when compared with the structurally distinct peptide VIP and PGE1.

Adrenomedullin↗

PubMed2003

Reactive nitrogen species scavenging, rather than nitric oxide inhibition, protects from articular cartilage damage in rat zymosan-induced arthritis.

1. The contribution of nitric oxide (NO) and peroxynitrite (PN) to inflammation in a zymosan-induced (1 mg, intra-articular, i.art.) rat model of arthritis was assessed by histopathology and by measuring the glycosaminoglycan (GAG) content of the articular cartilage. 2. Progression of the chronic synovitis in zymosan-induced arthritis (ZYA) was associated with increased nitrite and nitrotyrosine (3-NT) levels in the joint exudates that paralleled a progressive loss of the GAG content. An increase in 3-NT was also observed after i.art. PN. 3. The nonselective nitric oxide synthase (NOS) inhibitor l-N(G)-nitroarginine methyl ester (25-75 mg x kg(-1)day(-1)) or the selective inducible NOS inhibitor aminoguanidine (50-100 mg x kg(-1)day(-1)) given 1 h before (prophylactic) or 3 days after (therapeutic) injection of the zymosan ameliorated the synovitis, but worsened the GAG loss, as measured at the end of the experiment (day 7). 4. The PN scavenger uric acid (100-250 mg x kg(-1) i.p. four times daily) given prophylactically until the end of the experiment (day 14), in a dose compatible with its PN scavenging activity, significantly decreased both the synovitis and the GAG loss. 5. In conclusion, PN formation is associated with cartilage damage in addition to proinflammatory activity in ZYA. NOS inhibitors and a PN scavenger were able to reduce the cellular infiltration, while displaying opposite effects on cartilage homeostasis either by enhancing or ameliorating the damage, respectively.

Animals↗

PubMed2003

The ability of neuropeptide Y to mediate responses in the murine cutaneous microvasculature: an analysis of the contribution of Y1 and Y2 receptors.

1. The ability of neuropeptide Y (NPY) to modulate skin blood flow, oedema formation and neutrophil accumulation was investigated. Experiments were designed to examine the possible contribution of the Y2 receptor, in addition to the Y1 receptor, through use of Y2 receptor knockout mice (Y2-/-) and selective receptor antagonists. 2. The development of a 99mTc clearance technique for the measurement of microvascular blood flow changes in mouse dorsal skin revealed a dose-dependent ability of picomole amounts of NPY, and also of the Y1-preferred agonist Pro34NPY and the Y2-preferred agonist PYY(3-36) to decrease blood flow. 3. The Y1 receptor antagonist BIBO3304 blocked responses to the Y1 agonist at the lower doses, but only partially inhibited at the higher doses tested in Y2+/+. In Y2-/- receptor mice, the responses to the Y2 agonist were abolished at the lower doses and partially reduced at the highest dose tested, while those to the Y1 agonist were similar in both Y2+/+ and Y2-/-receptor mice. 4. In Y2+/+ receptor mice, the simultaneous injection of the Y2 antagonist BIIE0246 with BIBO3304 abolished Y2 agonist-induced decreases in blood flow over the dose range used (10-100 pmol). When the Y2 receptor antagonist BIIE0246 was given alone, it was not able to significantly affect the PYY(3-36)-induced response, whereas the Y1 receptor antagonist BIBO3304 partially (P<0.001) inhibited the decrease in blood flow evoked by PYY(3-36) at the highest dose. 5. NPY did not mediate either oedema formation, even when investigated in the presence of the vasodilator calcitonin gene-related peptide (CGRP), or neutrophil accumulation in murine skin. 6. We conclude that the major vasoactive activity of NPY in the cutaneous microvasculature is to act in a potent manner to decrease blood flow via Y1 receptors, with evidence for the additional involvement of postjunctional Y2 receptors. Our results do not provide evidence for a potent proinflammatory activity of NPY in the cutaneous microvasculature.

Animals↗

PubMed2003

Endothelial cells play an essential role in the thermal hyperalgesia induced by nerve growth factor.

Nerve growth factor (NGF) is a potent mediator of inflammatory hyperalgesia, in addition to roles in the development and maintenance of neurons. We provide evidence for the novel concept that microvascular endothelial cells play a critical primary role in NGF-mediated events that lead to inflammatory hyperalgesia in rat skin. We show that, surprisingly, neutrophils are not directly activated by NGF, although local administration of NGF mediates thermal hyperalgesia via mechanisms involving concomitant neutrophil accumulation. The co-administration of actinomycin D with NGF negated both neutrophil accumulation and thermal hyperalgesia, indicating the dependence of NGF on local de novo protein synthesis. More significantly, an antibody against the endothelial-derived adhesion molecule ICAM-1 also blocked neutrophil accumulation and thermal hyperalgesia. Finally the ability of NGF to stimulate ICAM-1 in human cultured umbilical vein endothelial cells is shown. We propose that NGF acts primarily to activate endothelial cells and that this response is essential for the ensuing neutrophil accumulation and hyperalgesia. The findings reveal a central role of the endothelial cell in initiating NGF-dependent inflammatory hyperalgesia and emphasize the importance of further investigations aimed at examining the feasibility of new therapeutic strategies that target NGF.

Animals↗

PubMed2003

Functional significance of inducible nitric oxide synthase induction and protein nitration in the thermally injured cutaneous microvasculature.

Increased nitric oxide (NO) production after burn injury is well established. However, there is little information relating to the reactions that occur as a consequence of NO generation under such circumstances. We have investigated the synthesis and function of NO in a rat model of local cutaneous thermal injury. We show that NO levels are elevated from 3 hours after injury with a concomitant increase in protein nitration. A selective inducible nitric oxide synthase (iNOS) inhibitor (1400W) significantly attenuated NO synthesis, protein nitration, and neutrophil accumulation in this model, but had no effect on edema formation. The results also indicate that NO synthesis and protein nitration occurred independently of neutrophil accumulation because these parameters were unaffected by depletion of circulating neutrophils. 3-Chlorotyrosine, a marker of neutrophil/myeloperoxidase-mediated protein damage was significantly increased from 1 hour after burn. Our observations provide evidence for the involvement of reactive species in the inflammatory response after burn. The use of selective iNOS inhibitors may represent a novel approach for the management of human burn injuries.

Animals↗

PubMed2003

Basal and activity-induced release of substance P from primary afferent fibres in NK1 receptor knockout mice: evidence for negative feedback.

The concept that NK1 receptors are located pre-junctionally on substance P (SP)-containing nerves, acting as autoreceptors to inhibit SP release, has been suggested, but remains a controversial issue. To further investigate the existence of this receptor on central and peripheral terminals of primary afferent fibres, NK1 receptor knockout mice and an NK1 receptor antagonist were used in nerve-attached tissue preparations. These were the isolated dorsal horn of the spinal cord with dorsal roots attached, and the hairy skin of the hind paw with attached saphenous nerve. The results reveal that in the dorsal horn preparation, basal release of SP is significantly higher in NK1(-/-) mice than NK1(+/+) mice (P<0.05, n=7 mice/strain). However, a difference in SP release evoked in the dorsal horn by electrical stimulation of the dorsal roots or capsaicin application was not observed. In contrast, antidromic electrical stimulation of the saphenous nerve caused a substantially greater release of SP in the skin of NK1(-/-) mice than in NK1(+/+) mice (P<0.05, n=5 to 6 mice/strain). These results provide evidence for the existence of NK1 autoreceptors on sensory nerves in skin, which may be relevant to the modulation of their peripheral pathophysiological effector functions.

Afferent Pathways↗