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Role of protein kinase A in phosphorylation of NMDA receptor 1 subunits in dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats.

Protein phosphorylation is a major mechanism for regulation of N-methyl-D-aspartate (NMDA) receptor function. The NMDA receptor 1 subunit (NR1) is phosphorylated by protein kinase A (PKA) on serine 890 and 897. We have recently reported that there is enhanced phosphorylation of NR1 on serine 897 in dorsal horn and spinothalamic tract (STT) neurons after intradermal injection of capsaicin (CAP) in rats [Zou et al. (2000) J. Neurosci. 20, 6989-6997]. Whether or not this phosphorylation, which develops during central sensitization following CAP injection, is mediated by PKA remains to be determined. In this study, western blots and immunofluorescence staining were employed to observe if pretreatment with a PKA inhibitor, N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide, HCl (H89), blocks the enhanced phosphorylation of NR1 on serine 897 following injection of CAP into the glabrous skin of one hind paw of anesthetized rats. Western blots showed that pretreatment with H89 caused a decrease in CAP-induced phosphorylation of NR1 protein in spinal cord segments L(4)-S(1). In experiments using immunofluorescence staining, the numbers of phospho-NR1-like immunoreactive (p-NR1-LI) neurons seen after CAP injection were significantly decreased in the dorsal horn of the L(4)-L(5) segments on the side ipsilateral to the injection after PKA was inhibited. When STT cells were labeled by microinjection of the retrograde tracer, fluorogold, we found that the proportion of p-NR1-LI STT cells on the side ipsilateral to the injection in the superficial laminae of spinal cord segments L(4)-L(5) was markedly reduced when H89 was administered intrathecally before CAP injection. However, the proportion of p-NR1-LI STT cells in deep laminae was unchanged unless the PKC inhibitor, chelerythrine chloride, was co-administered with H89. Combined with our previous findings, the present results indicate that NR1 in spinal dorsal horn neurons, including the superficial dorsal horn STT cells, is phosphorylated following CAP injection and that this phosphorylation is due to the action of PKA. However, the phosphorylation of deep STT cells involves both PKA and PKC.

Animals↗

The CC chemokine MIP-1alpha induces a selective monocyte infiltration following intradermal injection into nonhuman primates.

The in vitro chemotactic activity of chemokines have been well documented. However, study of their in vivo effects where components of rolling, adherence and diapedesis are pre-requisites to leukocyte infiltration have not been examined in higher species. In this study, we examined the biological activity of the CC chemokine, MIP-1alpha, in rhesus monkeys. Following an intradermal injection, a significant cellular infiltrate and an increase in the number of inflamed vessels were observed. This response peaked at 24 h and was sustained for up to 48 hours after injection. Phenotypically, the specific infiltrate consisted exclusively of CD68+ monocytes with no increase in other cell types over the saline injected controls. These studies represent the first examination of the in vivo effects of MIP-1alpha in higher species and indicate that MIP-1alpha is a selective monocyte recruiting agent in vivo.

Animals↗

Increased microvascular permeability in vivo in response to intradermal injection of neutrophil-activating protein (NAP-2) in rabbit skin.

Neutrophil-activating protein-2 (NAP-2), an NH2-terminally processed form of the platelet-release product beta thromboglobulin (beta TG), was purified to homogeneity from stimulated human blood leukocytes. In the presence of a vasodilator substance (PGE2, CGRP) picomolar (pmol/l) amounts of NAP-2 induced neutrophil accumulation and plasma leakage on intradermal injection in rabbit skin, whereas the longer forms, beta TG itself and connective tissue-activating peptide III (CTAP-III), had no such effect. NAP-2-induced increased in microvascular permeability was neutrophil dependent and fast in onset, with a half-life of 65 to 75 minutes, comparable to that previously reported for the structural-related neutrophil-activating protein-1/interleukin-8 (NAP-1/IL-8). However NAP-2 showed a lower potency in that more protein was needed to provoke skin reactivity. Nevertheless the finding that a platelet release product can elicit neutrophil-mediated inflammation further narrows the gap between thrombotic events and inflammatory disorders.

Animals↗

Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function.

The ability of capsaicin to excite and subsequently to desensitize a select group of small sensory neurons has made it a useful tool to study their function. For this reason, application of capsaicin to the skin has been used for a variety of painful syndromes. We examined whether intradermal injection of capsaicin produced morphological changes in cutaneous nerve fibers that would account for its analgesic properties by comparing cutaneous innervation in capsaicin-treated skin with psychophysical measures of sensation. At various times after capsaicin injection, nerve fibers were visualized immunohistochemically in skin biopsies and were quantified. In normal skin the epidermis is heavily innervated by nerve fibers immunoreactive for protein gene product (PGP) 9.5, whereas fibers immunoreactive for substance P (SP) and calcitonin gene-related peptide (CGRP) are typically associated with blood vessels. There was nearly complete degeneration of epidermal nerve fibers and the subepidermal neural plexus in capsaicin-treated skin, as indicated by the loss of immunoreactivity for PGP 9.5 and CGRP. The effect of capsaicin on dermal nerve fibers immunoreactive for SP was less obvious. Capsaicin decreased sensitivity to pain produced by sharp mechanical stimuli and nearly eliminated heat-evoked pain within the injected area. Limited reinnervation of the epidermis and partial return of sensation occurred 3 weeks after treatment; reinnervation of the epidermis was approximately 25% of normal, and sensation improved to 50-75% of normal. These data show that sensory dysfunction after capsaicin application to the skin results from rapid degeneration of intracutaneous nerve fibers.

Adult↗

Assessment of leg oedema by dynamic lymphoscintigraphy with intradermal injection of technetium-99m human serum albumin and load produced by standing.

This study was a preliminary evaluation of the utility of dynamic lymphoscintigraphy with technetium-99m human serum albumin (HSA) and a load produced by standing in the assessment of lymphatic dysfunction in patients with leg oedema. The 71 subjects investigated included 53 patients with lymphoedema, six with venous occlusion alone and five with lymphovenous occlusion, as well as seven normal subjects. After intradermal injection of 99mTc-HSA into an interdigital space in each foot, dynamic scintigrams were recorded with the patient supine for 15 min. The subjects then stood in place and images were recorded for an additional 15 min. Relative changes in lymphatic tracer transport before and after standing were analysed on time-activity curves (TACs). This test was compared with a conventional test in a supine position in six patients with lymphoedema, and was repeated in five other patients with lymphoedema. It was found that in the normal limbs, a standing load activated tracer transport to the draining lymphatic vessels, resulting in a rapid stepwise increase in tracer activity, large spiking waves and a decreasing phase following a peak in tracer activity on TACs. In 59 lymphoedematous limbs, including some with a mild form of oedema without morphological abnormalities on scintigrams, this load failed to induce a sufficient activation of tracer transport, and the frequencies of each of the three normally appearing changes described above significantly decreased compared with those in the 14 normal limbs (P < 0.0001, P < 0.01 and P < 0.0001, respectively). In addition, there were significant reductions in the relative increases in maximum activity and clearance times after standing (both P < 0.0001). These abnormalities significantly correlated with the grade of severity of oedema. Six limbs with lymphovenous occlusion showed significant reductions in tracer transport compared to six limbs with venous occlusion. Lymphatic dysfunction was accentuated more by this test than by the conventional test, and repeated tests showed consistent results in the same individuals. It is concluded that under a standardized load, this quick test seems of value in providing a sensitive and objective assessment of lymphatic dysfunction in the lower limbs, and is also advantageous for image interpretation since accelerated tracer transport clearly visualizes compromised lymphatics. This test may also be helpful in distinguishing purely venous oedema from mixed lymphovenous disease.

Adult↗

Immature human monocyte-derived dendritic cells migrate rapidly to draining lymph nodes after intradermal injection for melanoma immunotherapy.

Injected antigen-loaded immature monocyte-derived dendritic cells (DCs) may be incapable of migrating from skin to draining lymph nodes for antigen presentation. The in vivo migratory capacity of intradermally administered immature monocyte-derived DCs was therefore investigated during a phase I/II clinical trial for metastatic melanoma. DCs cultured from adherent monocytes in the presence of autologous serum, granulocyte-macrophage colony stimulating factor and interleukin-4 were pulsed with antigen and labelled with technetium-99m hexamethylpropylene-amineoxime (99mTc-HMPAO) ex vivo, then injected intradermally. A 99mTc-HMPAO control containing an equivalent amount of radioactivity was injected into the opposite thigh. The pelvis was then imaged with a gamma camera. The DCs were characterized as immature by functional and phenotypic analysis. Labelled DCs travelled to the draining inguinal lymph nodes within 10 min, and the draining lymph nodes were clearly outlined up to 4 h after injection. Free NmTc outlined draining lymph nodes after 10 min but was cleared from the nodes within 1 h. Thus, immature human monocyte-derived DCs migrate rapidly to and remain in draining lymph nodes after intradermal injection for immunotherapy.

Adult↗

Successful induction of immune responses against mutant ras in melanoma patients using intradermal injection of peptides and GM-CSF as adjuvant.

The rapidly increasing incidence and mortality rate of malignant melanoma, together with the lack of efficient treatment of the late stages, makes it a serious threat to public health. Innovative new treatments are needed. The proteins of the ras-family of proto-oncogenes, functioning as relay switches for signalling pathways between cell surface and nucleus, are involved in cell proliferation, differentiation, apoptosis and transformation. If over-expressed or mutated they can induce and/or maintain a transformed state of a cell. Codon 61 mutations of N-ras seem to be involved in melanoma development on sun exposed sites. In order to induce an immune response towards mutated N-ras proteins we performed a phase 1 feasibility study. Ten melanoma patients were immunized intradermally 6 times with N-ras peptides (residue 49-73) with 4 codon 61 mutations using GM-CSF as adjuvant. HLA typing was not used as an inclusion criterion. Eight patients responded with strong delayed type hypersensitivity reactions. In 2 of the patients an in vitro response to the vaccine could also be detected. The specificity of the reaction could be confirmed by cloning of peptide-specific CD4 positive T cells from peripheral blood of the patients. Intradermal injection of ras peptides using GM-CSF as adjuvant is simple to perform and seems to be efficient in inducing cellular immune responses. Since a majority of the patients showed positive skin reactions and 2 of the patients analysed showed a T-helper response to this melanoma specific antigen, these promiscuous HLA class II binding mutant ras peptides may be candidates for inclusion into vaccine cocktails containing various established CTL epitopes.

Adjuvants, Immunologic↗

Increased phosphorylation of the GluR1 subunit of spinal cord alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor in rats following intradermal injection of capsaicin.

Ionotropic glutamate receptors are ligand-gated ion channels that help mediate rapid excitatory neurotransmission in the CNS. alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors are critical for synaptic plasticity in central nociceptive transmission. The current study was designed to investigate the role of the AMPA receptor subunit, GluR1, and its phosphorylated forms (at Ser-831 and Ser-845) in central sensitization in rat spinal cord. Western blots and immunohistochemistry were performed to examine the expression and localization of GluR1 and the phosphorylated forms of GluR1 (phospho-GluR1) at Ser-831 and Ser-845 with specific antibodies. Results showed that immunolabeling of GluR1 protein in rat spinal cord can be detected at 110 kD, and two phospho-GluR1 proteins were found at 106 kD. A significant upregulation of phospho-GluR1 both at Ser-831 and Ser-845 was found by 5 min after capsaicin treatment, and this increase lasted at least 60 min. Immunostaining showed that GluR1 and its phosphorylated forms were localized in the superficial laminae of dorsal horn and quantitative image analysis supported the immunoblotting results. Our findings are consistent with the suggestions that AMPA receptors show increased responsiveness because of their phosphorylation and that this may contribute to central sensitization following intradermal injection of capsaicin.

Animals↗

Strain differences in local hemorrhagic response (Shwartzman-like reaction) of mice to a single intradermal injection of bacterial polysaccharides.

A survey of inbred strains of mice was made to determine whether the phenomenon of dermal hemorrhagic necrosis, as described in rabbits by Shwartzman, could be elicited in mice by bacterial polysaccharide preparations of demonstrated activity in rabbits. The polysaccharide preparations used were obtained from cultures of S. marcescens, S. typhosa, Ps. aeruginosa, and H. pertussis. Ten of the strains tested were unreactive. Three strains of mice and one F(1) hybrid subline developed a hemorrhagic lesion at the site of injection of a single, relatively high intradermal dose of polysaccharide. Some increase in incidence of hemorrhagic lesions was obtained when the intradermal dose was followed in 24 hours by an intravenous injection. In the gross and microscopically, the skin lesion produced in mice resembled the Shwartzman reaction in rabbits. An adrenergic blocking agent, SY-28, and an anticoagulant drug, coumadin, both of which block the dermal Shwartzman reaction in rabbits, also blocked the hemorrhagic skin reaction in mice.

Animals↗

The ACVD task force on canine atopic dermatitis (VI): IgE-induced immediate and late-phase reactions, two inflammatory sequences at sites of intradermal allergen injections.

Intradermal testing is a common diagnostic procedure used in the evaluation of dogs with suspected atopic dermatitis (AD). To do this, most investigators assess the appearance of wheals that develop at the sites of intradermal allergen injections. However, wheals are rarely seen in dogs with naturally occurring AD. Furthermore, infiltration of inflammatory cells into the injection sites can occur 6-24h later, a phenomenon known as the late-phase reaction. The histological appearance of these late-phase reactions closely approximates that seen in the natural disease, suggesting that they might be more relevant than the immediate reactions. In this paper, we review the literature on immediate and late-phase reactions and re-assess the evidence for using current intradermal testing procedures as a diagnostic test in dogs.

Allergens↗

Laser Doppler imager (LDI) scanner and intradermal injection for in vivo pharmacology in human skin microcirculation: responses to acetylcholine, endothelin-1 and their repeatability.

AIMS: The purpose of this study was to evaluate the repeatability of forearm skin blood flow responses to intradermal injections of acetylcholine (ACh) and endothelin-1 (ET-1) using a double injection technique (DIT) and a laser Doppler imager (LDI) scanner in the human skin microcirculation. METHODS: We used a laser Doppler imager (Moor LDI V3.01) to continuously monitor the change in skin blood flow during intradermal administration of physiological saline (0.9% NaCl), acetylcholine (ACh 10(-7), 10(-8), 10(-9) M) and endothelin-1 (ET-1 10(-14), 10(-16), 10(-18) M) in 10 healthy male subjects. Subjects were examined on 3 different days for assessment of interday and interobserver repeatability. Injections of either drug were randomly placed on different sites of the forearm. Laser Doppler images were collected before and after injection at 2.5 min intervals for 30 min. Data were analysed after the completion of each experiment using Moor Software V.3.01. Results are expressed as changes from baseline in arbitrary perfusion units (PU). RESULTS: ACh caused a significant vasodilation (P < 0.0001 anova, mean +/- SE: 766 +/- 152 PU, ACh 10(-9) M; 1868 +/- 360 PU, ACh 10(-8) M; 4188 +/- 848 PU, ACh 10(-7) M; mean of days 1 and 2, n = 10), and ET-1 induced a significant vasoconstrictive response (P < 0.0001 anova, -421 +/- 83 PU, ET-1 10(-18) M; -553 +/- 66 PU, ET-1 10(-16) M; -936 +/- 90 PU, ET-1 10(-14) M; mean of days 1 and 2, n = 10). There was no difference on the response to either drug on repeated days. Bland-Altman analyses showed a close agreement of responses between days with repeatability coefficients of 1625.4 PU for ACh, and 386.0 PU for ET-1 (95% CI: ACh, -1438 to 1747 PU, ET-1, -399 to 358 PU) and between observers with repeatability coefficients of 1057.2 PU for ACh and 255.8 PU for ET-1 (95% CI: ACh, -1024 to 1048 PU, ET-1, -252 to 249 PU). The variability between these responses was independent of average flux values for both ACh and ET-1. There was a significant correlation between responses measured in the same site, in the same individual on two different days by the same observer (ACh, r = 0.94, P < 0.0001; ET-1, r = 0.90, P < 0.0006), and between responses measured by two different observers (ACh, r = 0.94, P < 0.0001; ET-1, r = 0.91, P < 0.0003). CONCLUSION: We have shown that interday and intraobserver responses to intradermal injections of ET-1 and ACh, assessed using the DIT in combination with an LDI scanner, exhibited good reproducibility and may be a useful tool for studying the skin microcirculation in vivo.

Acetylcholine↗

Pain and inflammatory hyperalgesia induced by intradermal injections of human platelets and leukocytes.

Acute and prolonged inflammatory processes, induced by intradermal injections of autologous platelet preparations, leukocytes, platelet-leukocyte mixtures and vehicle solutions, were monitored in 20 human subjects for up to 48 h. Psychophysical methods were employed to assess the time course of pain response, and the development of hyperalgesia. Time course of the axon reflex erythema was analysed by computer based videography. Injections of functionally intact platelets [4.4 x 10(7)+/- 0.6 x 10(7)in 50 µl (mean +/- SEM)] caused distinct pain sensations [median pain rating 7.25 (25-75%: 6.5-7.5) on a scale form 0-10]. Both platelets injected through a microfilter (0.2 µm) and heat-inactivated platelets induced similar initial pain response; however, pain duration was significantly shorter than for intact platelets. Control injections of leukocytes (5.4 x 10(6)+/- 3.7 x 10(6)in 50 µl) and of vehicle solutions only caused minute pain sensations.Although platelet concentration in the mixture was only 50%, platelet/leukocyte mixtures produced axon reflex erythema that were significantly larger than those seen with naive platelets alone (11.1 +/- 2.3 vs 8.3 +/- 0.8 cm(2)). Intact platelets and heat-inactivated platelets both induced mechanical hyperalgesia and skin indurations at the injection site. Both reactions peaked between 6 and 24 h after the injection and disappeared within 48 h. Neither hyperalgesia, nor the development of indurations was noted at the injection sites of filtered platelets and vehicle solutions. Leukocyte injections induced hyperalgesia and indurations only in samples with a platelet contamination of more than 50 000 cells/µl. We conclude that platelets induce acute pain responses due to a soluble factor, whereas the development of hyperalgesia and the formation of indurations depends on a membrane-bound factor. Moreover, platelets and leukocytes act synergistically in nociceptor activation. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.

Journal Article↗

The effects of protein phosphatase inhibitors on nociceptive behavioral responses of rats following intradermal injection of capsaicin.

The functions of crucial proteins in the nervous system are modulated by kinases and phosphatases which catalyze opposing reactions of phosphorylation and dephosphorylation. During spinal cord central sensitization, serine/threonine protein phosphatase 2A (PP2A) may play an important role in determining the excitability of nociceptive neurons in the spinal cord by modulating the phosphorylation state of some critical proteins. The effects of a general inhibitor of PP2A, okadaic acid (OA), and a specific inhibitor, fostriecin, on the behavioral responses of rats following capsaicin injection were investigated in this study. Hyperalgesia was initiated by injection of capsaicin into the plantar surface of the hindpaw of rats. An intrathecal catheter was previously implanted into the subarachnoid space of the spinal cord for the administration of a variety of drugs. Rats were tested for responses to mechanical stimuli using von Frey filaments of different bending forces applied at a site outside the area of injection. Responses to heat stimuli were detected from a site near the injection area. The responses were recorded before and after injection of capsaicin with the perfusion of ACSF, OA negative control, OA or fostriecin at different time points. The results demonstrated that secondary mechanical hyperalgesia and allodynia can be induced by the intradermal injection of capsaicin. Compared to administration of ACSF or the OA negative control, infusion of the phosphatase inhibitor OA or of fostriecin into the subarachnoid space enhanced the secondary mechanical hyperalgesia and allodynia by making the intradermal capsaicin-induced hyperalgesia and allodynia last longer.

Animals↗

Pharmacokinetic studies in Tg.AC and FVB mice administered [14C] benzene either by oral gavage or intradermal injection.

Chronic benzene toxicity has been demonstrated to result in either aplastic anemia or acute myelogenous leukemia, a form of granulocytic leukemia, in exposed people (Snyder and Kalf, Crit. Rev. Toxicol. 24, 177-209, 1994). Aplastic anemia has been demonstrated in animal models following benzene exposure but, heretofore, it has not been possible to replicate benzene-induced granulocytic leukemia in animals. The Tg.AC mouse appears to be the first animal model in which a granulocytic leukemia was produced by treatment with benzene (Tennant et al., The Use of Short- and Medium-Term Tests for Carcinogenic Hazard Evaluation, 1999; French and Saulnier, J. Toxicol. Environ. Health 61, 377-379, 2000). Leukemia was observed in Tg.AC mice to which benzene was administered dermally. Neither orally dosed Tg.AC mice or mice of the parental FVB strain treated by either route of exposure developed leukemia. It is well established that benzene metabolism is required to produce benzene toxicity. To determine whether metabolic differences arising from differences in route of exposure or strain of mouse directed the development of leukemia, the pharmacokinetics of benzene were compared between the two strains and between the two routes of administration. Regardless of the route of exposure or the strain of mouse, seven major metabolites plus unmetabolized benzene were detected in most samples at most time points. Few differences were observed between the two strains following either route of administration. These results suggest that the genetic modification in the Tg.AC mouse, i.e., insertion of the v-Ha-ras construct into the genome, did not disrupt any major pathways involved in determining the pharmacokinetics of benzene. Two significant differences were observed between the two routes of exposure: first, benzene was absorbed more slowly after intradermal injection than after oral gavage, and second, the intradermally dosed mice produced more conjugates of hydroquinone than did the orally dosed mice. These differences in metabolism may be involved in the previously observed differences in hematotoxicity between the two routes of exposure.

Administration, Oral↗

[Satellite vasculitis of B or non-A non-B hepatitis. Diagnostic value of a provocation test by intradermal injection of histamine].

The histo-pathological lesions of hypersensitivity vasculitis (HV) consist in an inflammatory reaction to circulating immune complexes deposited on the vascular endothelium. A provocation test by intradermal injection of histamine was used to demonstrate HV in patients with chronic hepatitis. Three groups of patients were studied: 16 with chronic hepatitis and HV, 22 with chronic hepatitis without HV, 4 control subjects. Skin biopsy was performed before and 3 hours after intradermal histamine. The following markers were looked for in the serum, skin and liver of all patients with chronic hepatitis: HBV (HBs Ag and HBe Ag, anti-HBs, anti-HBe and anti-HBc in the serum, HBs and HBc Ag in the liver); non-A non-B (non-A, non-B Ag and antibody, anti non-A non-Bc in the serum, non-A, non-Bc Ag in the liver). Viral antigens were found in healthy skin in 2 cases (1 chronic A hepatitis, 1 vasculitis), and after injection of histamine in 9 cases (4 chronic A hepatitis, 5 vasculitis). Viral antigens were found on skin biopsy in 2 patients with negative sera. Significant skin changes after histamine were detected only in HV (75 p. 100) even in the absence of cutaneous vasculitis (6/12 positive cases). An intradermal histamine provocation test is a simple, non-invasive method for diagnosing HV.

Hepatitis, Chronic↗

Mechanism of local skin atrophy caused by intradermally injected corticosteroids.

Different hydrocortisone microcrystal suspensions applied intradermally in rabbits caused skin atrophy. This could be ascribed to secondary tissue degeneration as was ascertained histologically. The degree of degeneration was related to the concentration of the suspension, size of the microcrystals and frequency of the intervals between the injections. The ground substance of the connective tissue changes and is characterized by a basophilic granular mass, homogenized collagen fibers and degeneration of the elastic fibers. The pathomechanism of local skin atrophy not only differs from connective tissue degeneration caused by systemic corticosteroid treatment but also from the degeneration caused by topical treatment.

Animals↗

Immune response to intradermally injected inactivated poliovirus vaccine.

Immune response to intradermal inoculation of a fractional dose of inactivated poliovirus vaccine (IPV) was measured in 8 adults and 10 children who were previously immune. A striking 4-fold to 1024-fold antibody booster response to all 3 poliovirus serotypes was found in 15 subjects and a similar response to 2 poliovirus serotypes occurred in the other 3 children. Induration and erythema of 3 mm diameter or above, indicative of a cell-mediated immune response, was seen in 12 subjects. Intradermal inoculation of IPV may be a useful technique for secondary immunisation programmes against polio and its use for primary immunisation merits investigation.

Adult↗

Biphasic vasomotor reflex responses of the hand skin following intradermal injection of melittin into the forearm skin.

Melittin is the main toxin of honeybee venom. Previously, we have reported that intradermal injection of melittin into the volar aspect of forearm in humans produces a temporary pain and a subsequent sustained increase in the skin temperature due to axon reflex. To clarify the interaction between nociceptive inputs and vascular changes, we studied the influence of noxious stimulation by intradermal melittin on the vasomotor control of the distal extremities in human volunteers. Temperature changes of the bilateral palmar surface were recorded by means of a computer-assisted infrared thermography. Unexpectedly, we found a biphasic response of skin temperature. The skin temperature of both fingers and hands decreased immediately after the melittin injection and then increased well above the control level, prior to the injection. There was a considerable individual variation in the baseline skin temperature, prior to melittin. The skin temperature in a finger/hand with lower preinjection value increased more markedly in the second phase. Consequently, the individual variation in the peak temperature of the second phase was less pronounced. The initial decrease was interpreted as sympathetic vasoconstrictor reflex induced by noxious stimulation and the later increase as release of sympathetic vasomotor tone.

Adult↗