Two-stage laparoscopic transversus abdominis plane block as an equivalent alternative to thoracic epidural anaesthesia in bowel resection-an explorative cohort study.

PURPOSE: We evaluated the effect of the two-stage laparoscopic transversus abdominis plane block (TS-L-TAPB) in comparison to thoracic epidural anaesthesia (TEA) and a one-stage L-TAPB (OS-L-TAPB) in patients who underwent elective laparoscopic bowel resection. METHODS: We compared a TS-L-TAPB (266 mg bupivacaine), which was performed bilaterally at the beginning and end of surgery, with two retrospective cohorts. These were patients who had undergone a TEA (ropivacaine/sufentanil) or an OS-L-TAPB (200 mg ropivacaine) at the beginning of surgery. Oral and i.v. opiate requirements were documented over the first 3 postoperative days (POD). RESULTS: Patients were divided into three groups TEA (n = 23), OS-L-TAPB (n = 75), and TS-L-TAPB (n = 49). By the evening of the third POD, patients with a TEA had a higher cumulative opiate requirement with a median of 45.625 mg [0; 202.5] than patients in the OS-L-TAPB group at 10 mg [0; 245.625] and the TS-L-TAPB group at 5.625 mg [0; 215.625] (p = 0.1438). One hour after arrival in the recovery room, significantly more patients in the TEA group (100%) did not need oral and i.v. opioids than in the TS-L-TAPB (78%) and OS-L-TAPB groups (68%) (p = 0.0067).This was without clinical relevance however as the median in all groups was 0 mg. On the third POD, patients in the TEA group had a significantly higher median oral and i.v. opioid dose at 40 mg [0; 80] than the TS-L-TAPB and OS-L-TAPB groups, both at 0 mg [0; 80] (p = 0.0009). CONCLUSION: The TS-L-TAP showed statistically significant and clinically meaningful benefits over TEA and OS-L-TAP in reducing postoperative opiate requirements.

[Pilot study on subjectively and objectively measurable stress reduction in the daily routine of a university anesthesia department by an intervention program according to mindfulness-based stress reduction]. / Pilotstudie zu subjektiv und objektiv messbarer Stressreduktion im Alltag einer universitären Anästhesieabteilung durch ein Interventionsprogramm nach Mindfulness-Based Stress Reduction (MBSR).

BACKGROUND: Chronic stress and high workload in physicians can lead to loss of interest, emotional exhaustion and finally in burnout syndrome. This can cause serious consequences not only for the physicians personally and their own health by developing extensive health impairments, e.g. depression, suicide, substance abuse and poor self-care but also for patient care, reflected in an increase of medical errors, longer recovery times, lower care quality and consequently lower patient satisfaction. Additionally, it can also have negative effects on the healthcare system by reduced productivity, increased physician turnover and thereby higher costs. OBJECTIVE: This pilot study investigated brief interventions inspired by mindfulness-based stress reduction (MBSR) combined with short daily meditation exercises in the everyday work of anesthetists at a university hospital. Secondly, whether this program increases the development of coping mechanisms for stress and improves participants' resilience and health status. MATERIAL AND METHODS: The pilot study was designed as a monocenter prospective interventional study with four different points of measurement. Subjective and objective stress parameters were measured directly before (t0) and after (t1) the intervention as well as 3 (t2) and 6 (t3) months after end of the intervention. Measurements took place during work time and at the workplace. The intervention was based on the classical MBSR including short daily exercises and lasted for 6 weeks with sessions lasting 1- 1.5 h and an additional 20 min of daily mediation exercises. The subjective parameters were based on validated questionnaires, such as the World Health Organization (WHO) well-being index (WHO-5), resilience scale (RS-11), Maslach burnout inventory (MBI-22) and perceived stress scale (PSS-10). For objective parameters heart rate variability (HRV) was evaluated during rest and after exposure to physical exercise and hair cortisol concentrations (HCC) in a 1.5 cm length of a hair, which represents the equivalent of a 6-week period. RESULTS: Data from 27 subjects could be analyzed. Between t3 and t0 a significant improvement of resilience was detected as a positive personality trait measured by RS-11 with a large effect size (p = 0.013; r = 0.59) as well as a significant reduction of burnout symptoms (MBI-22) also with a large effect size (p = 0.019; r = 0.57). Furthermore, a significant decrease was found in well-being (WHO-5) between t2 and t0 (p = 0.003, r = 0.67) and between t1 and t0 (p = 0.001, r = 0.71). The objective parameters did not show any significant differences between the examinations. CONCLUSION: An MBSR-based intervention in combination with short exercises during and after work can be implemented in daily work of anesthetists at a university hospital. Furthermore, there was clear evidence that the intervention program increased resilience and reduced burnout symptoms for up to 6 months. These findings are in line with the literature that MBSR reduces risk of burnout symptoms. The decrease in well-being might be biased by a high amount of socially accepted answers at the beginning of the study (t0).

Treatment history and placebo responses to experimental and clinical pain in chronic pain patients.

BACKGROUND: Placebo analgesia refers to the reduction in pain due to the administration of an inert treatment. It is induced by expectations of pain relief which are enhanced by learning mechanisms. In healthy humans, prior positive experiences enhance the placebo response. However, the effects of patients' prior experiences with treatment on placebo responses have not yet been examined. This study investigated how verbal information, learning and treatment history influence the magnitude of placebo analgesia in chronic pain. METHODS: We administered a pharmacological placebo intervention in a sample of chronic pain patients (n = 49) who were seeking treatment in an outpatient pain clinic. Analyses were based on placebo responders. RESULTS: We found that verbal information about a potent pain-relieving effect of the intervention induced a large placebo analgesic response to both acute experimental (F(1,44) = 43.35, p < 0.001) and chronic pain (F(1,44) = 37.72, p < 0.001). However, the placebo responses to experimental and chronic pain were not significantly related (r = 0.012, p = 0.95). An additional conditioning procedure did not significantly enhance placebo analgesia. Treatment history modulated the magnitude of the placebo response: patients with a more negative pain-related treatment history reported significantly larger placebo responses to their own chronic pain (τ = 0.271, p = 0.044). CONCLUSIONS: We could show that placebo responses to both acute and chronic pain are high in pain treatment settings and that treatment history modulates this effect. Different mechanisms might underlie placebo responses to acute and chronic pain. Our findings highlight the necessity of considering placebo responses and treatment history in the treatment of chronic pain. WHAT DOES THIS STUDY ADD?: Placebo analgesia following verbal information of potent pain relief is high in chronic pain patients in a clinical setting. It is modulated by treatment history. Different mechanisms might underlie placebo analgesia to acute and chronic pain.

Laser-evoked potentials mediated by mechano-insensitive nociceptors in human skin.

OBJECTIVES: Laser-evoked potentials (LEP) were assessed after peripheral nerve block of the lateral femoral cutaneous nerve (LFCN) in healthy volunteers from partially anesthetized skin areas to differentially stimulate mechano-insensitive nociceptors. METHODS: An ultrasound-guided nerve block of the LFCN was performed in 12 healthy male subjects with Ropivacain 1%. After 30 min, the nerve block induced significantly larger anesthetic areas to mechanical stimuli than to electrical stimuli revealing an area of differential sensitivity. LEPs, reaction times and pain ratings were recorded in response to the laser stimuli of (1) completely anesthetic skin, (2) mechano-insensitive, but electrically excitable skin ('differential sensitivity'), (3) normal skin. RESULTS: LEP latencies in the area of differential sensitivity were increased compared to unaffected skin (228 ± 8.5 ms, vs. 181 ± 3.6 ms, p < 0.01) and LEP amplitudes were reduced (14.8 ± 1.2 µV vs. 24.6 ± 1.7 µV, p < 0.01). Correspondingly, psychophysically assessed response latencies in the differentially anesthetic skin were increased (649 ms vs. 427 ms, p < 0.01) and pain ratings reduced (1.5/10 vs. 5/10 NRS, p < 0.01). CONCLUSION: The increase in LEP latency suggests that mechano-insensitive heat-sensitive Aδ nociceptors (MIA, type II) have a slower conduction velocity or higher utilization time than mechano-sensitive type II Aδ nociceptors. Moreover, widely branched, slowly conducting and mechano-insensitive branches of Aδ nociceptors can explain our finding. LEPs in the differentially anesthetized skin provide specific information about a mechanically insensitive but heat-sensitive subpopulation of Aδ nociceptors. These findings support the concept that A-fibre nociceptors exhibit a similar degree of modality specificity as C-fibre nociceptors.

Mechano-sensitive nociceptors are required to detect heat pain thresholds and cowhage itch in human skin.

BACKGROUND: Mechano-sensitive and mechano-insensitive C-nociceptors in human skin differ in receptive field sizes and electrical excitation thresholds, but their distinct functional roles are yet unclear. METHODS: After blocking the lateral femoral cutaneous nerve (NCFL) in eight healthy male subjects (3-mL Naropin(®) 1%), we mapped the skin innervation territory being anaesthetic to mechanical pin prick but sensitive to painful transcutaneous electrical stimuli. Such 'differentially anaesthetic zones' indicated that the functional innervation with mechano-sensitive nociceptors was absent but the innervation with mechano-insensitive nociceptors remained intact. In these areas, we explored heat pain thresholds, low pH-induced pain, cowhage- and histamine-induced itch, and axon reflex flare. RESULTS: In differentially anaesthetic skin, heat pain thresholds were above the cut-off of 50°C (non-anaesthetized skin 47 ± 0.4°C). Pain ratings to 30 µL pH 4 injections were reduced compared to non-anaesthetized skin (48 ± 9 vs. 79 ± 6 VAS; p < 0.01). The axon reflex flare area did not differ between these zones (7.8 ± 1.4 cm(2) vs. 8.3 ± 0.5 cm(2) ). Histamine iontophoresis still caused pruritus in differentially anaesthetized skin in five of eight subjects (VAS 26 ± 14), whereas itch upon cowhage spicules was absent (VAS 0 vs. 29 ± 11 in non-anaesthetized skin). CONCLUSIONS: We conclude that activation of mechano-insensitive nociceptors is sufficient to provoke itch by histamine- and acid-induced pain. The mechano-sensitive nociceptors are crucial for cowhage-induced itch and for the assessment of heat pain thresholds.

[Interventional pain therapy. Results of a survey among specialized pain physicians in Germany]. / Interventionelle Schmerztherapie. Ergebnisse einer bundesweiten Umfrage unter speziellen Schmerztherapeuten.

BACKGROUND: Interventional pain therapy aims to treat pain which is refractory to pharmacologic and noninterventional treatment. Due to the partly lacking evidence and recommendations it remains unclear when interventional methods should be applied within the treatment pathway. This study assesses the current state of interventional methods in Germany and their leading indications comparing with the recommendations found in the literature. METHODS: An online survey was conducted among German physicians specialized in pain therapy concerning the number of interventions they perform per quarter, which supporting measures they use, and their indications for sympathetic blocks, sensory blocks, intrathecal administration, and spinal cord stimulation. RESULTS: A total of 109 physicians (23.5 %) participated in the survey. Blocks are most often performed on the stellate ganglion (94 %) and on the superior cervical ganglion (82 %). They are supported by anatomical landmarks and less often by imaging control. Both classic neuropathic pain diagnoses (e.g., complex regional pain syndrome) and diagnoses with a neuropathic pain component (e.g., peripheral arterial disease, tumor pain, and back pain) were considered as indications to perform interventional procedures. CONCLUSION: Although there is no clear evidence on interventional procedures in the current literature, these methods are often performed by the respondents. Anatomic landmarks are most frequently used for orientation. The German pain physicians who responded consider especially neuropathic pain as an indication to perform interventional procedures for pain therapy.

[Medical educational evaluation of the German Pain Congress 2012. In the context of the CanMEDS physician competency framework]. / Deutscher Schmerzkongress 2012 aus medizindidaktischer Sicht. Bewertung unter Berücksichtigung der im Rahmenmodell CanMEDS definierten Arztrollen.

BACKGROUND: Professionals in the medical field are expected to participate in continuing medical education in the sense of lifelong learning. The authors took this occasion to evaluate the most important national convention in pain medicine concerning its role in medical education. MATERIAL AND METHODS: The participants of the 37th German Pain Congress (17-20 October 2012 in Mannheim) were asked to complete a questionnaire concerning content and design of the convention. The aim of this study was to analyze the distribution of different physician competencies in the program. For this purpose the congress program was analyzed with respect to the various medical role models as defined in the Canadian medical education directions for specialists (CanMEDS) framework. RESULTS: The participants considered the quality of the different sessions of the German Pain Congress to be good. The poster sessions were considered to be the second most important educational format in the congress following the live sessions. Concerning the content of the congress the participants wished more emphasis on the role of interprofessional partners, such as nursing and psychotherapy. The CanMEDS physician roles of manager, communicator, health advisor and professional paragon were underrepresented in the congress program in this study. CONCLUSION: Regarding content and educational value, the congress design could benefit from additional Praktikerseminaren (practical seminars). The role of interprofessional partners should be more emphasized. In addition the program could become more attractive through a more balanced distribution of the CanMEDS roles.

[Cost minimization analysis in postoperative pain management : economic efficiency and effectiveness of two infusion pump systems]. / Kostenminimierungsanalyse in der postoperativen Schmerztherapie : Wirtschaftlichkeit und Effektivität von 2 Schmerzpumpensystemen.

BACKGROUND: Besides reliable efficacy and patient satisfaction, economic efficiency is becoming increasingly more important in postoperative pain management. AIM: The present study investigated the effectiveness of two pain pump systems and compared the running costs in treatment. MATERIAL AND METHODS: In this study 40 patients received an interscalene catheter prior to shoulder surgery. Postoperative pain management was provided via an electronic pump with patient-controlled analgesia (PCA) or a mechanical pump without PCA. Patients kept a pain log. After treatment they were interviewed about their satisfaction with the pump. In addition drug consumption, nursing material, staff time for handling and maintenance of the pumps and preparation of medications pro re nata were assessed. RESULTS: Postoperative pain levels and patient satisfaction were comparable in both groups. Economically, the electronic pump was more cost-effective than the electronic model for a duration of treatment of 1 and 2 days. With treatment duration of 2 days the costs of both pumps were equivalent; however, the PCA feature of the electronic pump allowed a reduced intake of systemic analgesics on demand. CONCLUSION: Both pain pump systems provide equally effective pain management, while the electronic model caused less costs. Both pumps offer advantages and disadvantages that should be considered based on local circumstantial demands.

[Cross-sectional field 14 pain medicine. Implementation of the German Pain Society (DGSS) core curriculum in the model study course MaReCuM]. / Querschnittsbereich 14 Schmerzmedizin. Umsetzung des Kerncurriculums der Deutschen Schmerzgesellschaft im Modellstudiengang MaReCuM.

BACKGROUND: The recent introduction of amendments to the medical licensure laws led to the introduction of the field of pain medicine into the study program "Human Medicine". The implementation has to be completed by all medical faculties before 2016. MATERIAL AND METHODS: Pain medicine was implemented into the model study course"MaReCuM" at the medical faculty in Manheim as a compulsory subject in the year 2010. It is structured into five sections in a longitudinal manner. The core section is the "pain awareness week" in the fifth academic year of the medical studies. The content and structure is based on the German Pain Society (DGSS) curriculum. For the purpose of this study the examination results and the student evaluation forms from the academic years 2010/2011 and 2011/2012 were analyzed. RESULTS: The students regarded pain medicine as being highly relevant concerning its impact on the professional activities. The competence to develop a specific and individual therapy was of special interest. A good coordination of the contents of teaching between preclinical and clinical teaching was considered to be of major importance. CONCLUSIONS: The DGSS curriculum is a useful tool for the implementation of pain medicine in a study program. In order to improve access to basic pain medicine in general, a combined teaching program consisting of pain medicine and general medicine could be helpful. Pain medicine could be used as a guide for teaching contents of outpatient medicine.

Skin innervation at different depths correlates with small fibre function but not with pain in neuropathic pain patients.

BACKGROUND: Neuropathy can lead not only to impaired function but also to sensory sensitization. We aimed to link reduced skin nerve fibre density in different levels to layer-specific functional impairment in neuropathic pain patients and tried to identify pain-specific functional and structural markers. METHODS: In 12 healthy controls and 36 patients with neuropathic pain, we assessed clinical characteristics, thermal thresholds (quantitative sensory testing) and electrically induced pain and axon reflex erythema. At the most painful sites and at intra-individual control sites, skin biopsies were taken and innervation densities in the different skin layers were assessed. Moreover, neuronal calcitonin gene-related peptide staining was quantified. RESULTS: Perception of warm, cold and heat pain and nerve fibre density were reduced in the painful areas compared with the control sites and with healthy controls. Warm and cold detection thresholds correlated best with epidermal innervation density, whereas heat and cold pain thresholds and axon reflex flare correlated best with dermal innervation density. Clinical pain ratings correlated only with epidermal nerve fibre density (r = 0.38, p < 0.05) and better preserved cold detection thresholds (r = 0.39, p < 0.05), but not with other assessed functional and structural parameters. CONCLUSIONS: Thermal thresholds, axon reflex measurements and assessment of skin innervation density are valuable tools to characterize and quantify peripheral neuropathy and link neuronal function to different layers of the skin. The severity of small fibre neuropathy, however, did not correspond to clinical pain intensity and a specific parameter or pattern that would predict pain intensity in peripheral neuropathy could not be identified.

[Neuropathic and tumour-induced headache: Therapeutic options]. / Neuropathischer und tumorbedingter Kopfschmerz : Therapieoptionen.

Cancer pain in the field of otolaryngology can be effectively alleviated. Only very few questions regarding the patient's history of pain are required to understand the type of pain being dealt with and to be able to make the correct selection of analgetic agents. It is particularly important to treat tumor breakthrough pain appropriately, for which a sufficient number of therapeutic agents are available. The present article comments on the various possibilities of specific drugs and interventional therapeutic approaches, as well as their specific characteristics within the field of otolaryngology, supplemented with various tricks for their practical application. Using these basic rules, most problems can be identified and specific treatments optimized. The progression of cancer pain may show wide dynamic ranges, and the therapeutic approach should always be adjusted to the current situation. Palliative care of a cancer patient may be particularly challenging in that, not only the treatment of pain, but also the treatment of respiratory distress is of key importance.

Anaesthesia for brachytherapy--51/2 yr of experience in 1622 procedures.

BACKGROUND: Brachytherapy presents the anaesthetist with unique problems. Information on anaesthesia for brachytherapy, however, is limited. The aim of this paper is to report on our experience involving a large number of brachytherapy procedures. METHODS: A retrospective analysis of records of 1622 anaesthetic procedures in 952 patients is presented. Records were analysed in respect of patient data, tumour localization, brachytherapy treatment and the type and duration of anaesthetic procedures. RESULTS: More than one-third of patients were at high risk (ASA III or IV) and 40% were more than 60 yr. Repetitive treatments were performed on half of the patients. Breast cancer was the most common indication. The average duration of anaesthesia for pelvic brachytherapy was more than 3 h, with a high degree of variability. Regional anaesthesia was used in 30% of all cases and was the predominant technique for pelvic brachytherapy. Spinal catheter techniques represented a high proportion of those receiving regional anaesthesia. Complications resulting from regional and general anaesthesia were minor and no serious incidents occurred. CONCLUSIONS: Based on a large number of procedures, this study gives an example of anaesthetic management in brachytherapy. A substantial minority of patients would be considered high risk for surgical intervention. Regional anaesthesia was the principal technique used when dealing with tumours of the lower body.

Low dose of S+-ketamine prevents long-term potentiation in pain pathways under strong opioid analgesia in the rat spinal cord in vivo.

BACKGROUND: micro-Opioid receptor (MOR) agonists are strong antinociceptive drugs. Low, but not high doses of the MOR agonist fentanyl prevent synaptic long-term potentiation (LTP) in pain pathways. Block of spinal N-methyl-D-aspartate (NMDA) receptors prevent central sensitization. Here we tested whether the NMDA receptor antagonist S(+)-ketamine reduces C-fibre-evoked potentials and prevents induction of LTP despite high doses of fentanyl. METHODS: C-fibre-evoked field potentials were recorded in the superficial laminae I/II of the rat lumbar spinal cord. High-frequency stimulation (HFS) was applied to the sciatic nerve at C-fibre strength to induce LTP. S(+)-ketamine 5 mg kg(-1) was given 1 h before or after HFS. S(+)-ketamine 5 mg kg(-1) and fentanyl as a bolus (40 microg kg(-1)) followed by an infusion (96 microg kg(-1) h(-1)) were given before HFS to test the action of the combination of these drugs. RESULTS: HFS potentiated C-fibre-evoked field potentials to mean 173 (sem 15)% of control (n=7) for at least 1 h. Low-dose S(+)-ketamine given before HFS blocked the induction of LTP. S(+)-ketamine given after HFS had no effect on the maintenance of LTP. Low-dose S(+)-ketamine prevented induction of LTP under fentanyl-infusion. CONCLUSIONS: Low-dose S(+)-ketamine does not affect C-fibre-evoked potentials alone but blocks LTP induction in pain pathways. In contrast, high doses of opioids strongly reduce C-fibre-evoked potentials, but do not fully prevent LTP induction. In this animal study the combination of S(+)-ketamine with fentanyl reveals both a reduction of C-fibre-evoked potentials and prevention of LTP and seem therefore a better choice for perioperative pain management compared with the sole administration.

Long-term intrathecal S(+)-ketamine in a patient with cancer-related neuropathic pain.

Neuropathic pain sometimes needs invasive pain therapy. We present the case of a patient with cancer-related neuropathic pain untreatable with conventional pain therapy after tumour-embolization. The patient was treated successfully with intrathecal (i.t.) administration of S(+)-ketamine, in addition to morphine. Plasma concentrations of S(+)-ketamine were measured regularly throughout the treatment. Continuous i.t. administration of S(+)-ketamine over a period of 3 months demonstrated low plasma levels and no unwanted side-effects.

Differential time courses of skin blood flow and hyperalgesia in the human sunburn reaction following ultraviolet irradiation of the skin.

The response of skin to ultraviolet (UV) irradiation is an inflammation with pronounced vasodilation and hyperalgesia. Volunteers underwent UV irradiation of patches of forearm skin 3 cm in diameter. The intensity of the UV irradiation (290-320 nm) ranged between 133 mJ/cm2 and 400 mJ/cm2. Changes in skin blood flow were measured with laser Doppler technique at 3, 6, 9, 12, 24, 30, 36, 48, 60, 72, 96 and 216 h post UV irradiation. The alteration in pain threshold was measured for heat with a Peltier thermode and for pressure with a metal stylus. The effect of repeated topical pre-treatment 4 days prior to UV irradiation with 1.5 g of 0.04% capsaicin containing ointment was also investigated.UV irradiation resulted in a dose-dependent increase of skin blood flow for more than 96 h post-irradiation. There were two peaks of blood flow at 12 h and 36 h. Topical application of capsaicin prior to UV irradiation attenuated blood flow from 30 h to 45 h post UV irradiation. Enhanced blood flow was also present 5 mm outside the irradiated area (flare reaction). The control level of heat pain threshold was 44.5+/-0.7;C in normal skin. Heat pain thresholds were lowered by up to 7.761.2;C in UV-irradiated areas in a dose-dependent fashion. The control level of pressure pain threshold was 15.260.3N. Pressure pain thresholds were lowered by up to 6 N in irradiated areas. Maximal hyperalgesia coincided with the second peak of skin blood flow between 30 h and 60 h post UV irradiation. The effects of topical application of capsaicin suggests an involvement of neuropeptide mechanisms in the late phase of the human sunburn reaction.

[Nociception in newborn and premature babies]. / Nozizeption bei Früh- und Neugeborenen.

BACKGROUND: The somatosensory system of preterms and newborns differs substantially from adults. These differences are of considerable preclinical and clinical interest. Maturation of A- and C-fibre synaptic connections in the dorsal horn and development of descending inhibition from the brainstem all take place postnatally in the rat. In early stages of development there is no definite spatial separation in the dorsal horn between the nociceptive and the non-nociceptive system. In preterms but not in adults non-noxious stimuli can induce central sensitization. Many neurotransmitters and signalling molecules involved in pain pathways are expressed early in the developing nervous system but do not reach adult levels for a considerable period. More important, receptors are frequently transiently overexpressed or expressed in areas during development where they are not seen in the adult and may have a different functional profile. The descending pain inhibitory system that provides an important protection against central sensitization develops later than the ascending nociceptive system. Thus, during a critical period of time the immature nociceptive system is highly vulnerable. For example, neonatal circumcision in the absence of analgesia results in increased pain responses during subsequent routine vaccination months later. CONCLUSIONS: In view of the changing nature of neonatal somatosensory and pain pathways and the vulnerability of the developing nervous system to alterations in sensory stimulation it is important that preterms and newborns need the care of a specialist for prevention and treatment of pain to avoid suffer and long-term changes in the nervous system.

Calcitonin gene-related peptide and nitric oxide are involved in ultraviolet radiation-induced immunosuppression.

Contact hypersensitivity responsiveness to dinitrofluorobenzene is depressed in mice that are sensitized through skin sites exposed to ultraviolet (UV) radiation. Local impairment of contact hypersensitivity by UV has been associated with a reduction in antigen-presenting cell activity within UV-irradiated skin sites marked by a decrease in the density of Ia-positive epidermal Langerhans cells. Our recent studies have demonstrated that neurogenic mediators (e.g. calcitonin gene-related peptide (CGRP) and nitric oxide (NO) contribute to cutaneous inflammation following exposure of rats to high-dose UV radiation. Since CGRP and NO inhibit antigen presentation by dendritic cells in vitro, we have investigated the possible involvement of CGRP and NO in local immunosuppression in UV-irradiated rodents. Hindpaw skin of Sprague-Dawley rats and back skin of UV-susceptible C57BL/6 mice was exposed to acute UV radiation (2.0 J/cm2 and 0.5 J/cm2, respectively). Alterations in cutaneous CGRP content were analyzed by a specific radioimmunoassay (RIA). In separate experiments, the CGRP receptor antagonist CGRP-(8-37) (10-5 M) and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (2 X 10-5 M) were topically applied to UV-exposed skin before induction of contact hypersensitivity with dinitrofluorobenzene. Finally, we examined the effects of UV irradiation and epicutaneous application of CGRP on Ia-positive Langerhans cells by immunohistochemical analysis of epidermal sheets. It was found that UV exposure lead to a decrease in skin CGRP levels starting already 2 h after irradiation and reaching a minimum (less than 40% of non-irradiated control skin) at 6-12 h. Contact hypersensitivity reactions were significantly suppressed by UV radiation in rat skin (by 51%) and murine skin (by 80%). Topical administration of both CGRP-(8-37) and L-NAME before sensitization restored the capacity to respond to haptens applied to UV-exposed skin. Both UV exposure and topical CGRP reduced the density of Ia-positive epidermal cells. Our data indicate that CGRP may be released from sensory neurons following cutaneous UV irradiation and that CGRP and NO contribute of UV-induced local immunosuppression. Moreover, topical administration of CGRP or its antagonist may be able to modulate epidermal Langerhans cell activity in vivo.