RESUMEN
Interferons (IFNs) are cytokines that possess antiviral, antiproliferative, and immunomodulatory actions. IFN-α and IFN-ß are two major family members of type-I IFNs and are used to treat diseases, including hepatitis and multiple sclerosis. Emerging evidence suggests that type-I IFN receptors (IFNARs) are also expressed by microglia, astrocytes, and neurons in the central and peripheral nervous systems. Apart from canonical transcriptional regulations, IFN-α and IFN-ß can rapidly suppress neuronal activity and synaptic transmission via non-genomic regulation, leading to potent analgesia. IFN-γ is the only member of the type-II IFN family and induces central sensitization and microglia activation in persistent pain. We discuss how type-I and type-II IFNs regulate pain and infection via neuro-immune modulations, with special focus on neuroinflammation and neuro-glial interactions. We also highlight distinct roles of type-I IFNs in the peripheral and central nervous system. Insights into IFN signaling in nociceptors and their distinct actions in physiological vs. pathological and acute vs. chronic conditions will improve our treatments of pain after surgeries, traumas, and infections.
Asunto(s)
Dolor Agudo/inmunología , Dolor Crónico/inmunología , Interferón Tipo I/metabolismo , Interferón gamma/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Dolor Agudo/patología , Animales , Dolor Crónico/patología , Modelos Animales de Enfermedad , Humanos , Neuroglía/citología , Neuroglía/inmunología , Neuroglía/patología , Enfermedades Neuroinflamatorias/patología , Nociceptores/inmunología , Nociceptores/metabolismo , Receptores de Interferón/metabolismo , Transducción de Señal/inmunología , Médula Espinal/citología , Médula Espinal/inmunología , Médula Espinal/patologíaRESUMEN
BACKGROUND: Amenamevir (AMNV) is a helicase-primase inhibitor with antiviral activity against herpesviruses [herpes simplex viruses (HSV)-1 and -2, and varicella-zoster virus], which are associated with the development of acute herpetic pain (AHP) and postherpetic neuralgia. However, the inhibitory effects of helicase-primase inhibitors on AHP and postherpetic neuralgia remain incompletely understood. OBJECTIVE: In this study, we investigated the effects of AMNV on AHP and postherpetic pain (PHP) in HSV-1-infected mice accompanied by zosteriform-like skin lesions. METHODS: HSV-1 was percutaneously infected on the femoral region of mice. AMNV was orally administered twice a day for 5 days. Pain-related response in the hind paw was evaluated using a paintbrush. The infiltration of inflammatory cells in dorsal root ganglion (DRG) and spinal cord (SC) was evaluated by hematoxylin and eosin staining. The viral load in DRG and the expression of pain-related genes in SC were measured by real-time PCR. RESULTS: Pain response was begun to be observed from day 3 post-infection (pi) in HSV-1-infected mice. AMNV administered repeatedly from day 3 pi or day 4 pi, but not day 5 pi, showed an inhibitory effect on the development of AHP and the transition to PHP. Repeated AMNV administration inhibited inflammatory cell infiltration and increases in the viral load and the expression of pain-related genes (ATF-3, TNF-α, COX-2). CONCLUSION: These results demonstrate that AMNV potently suppresses the development of AHP and the transition to PHP as a consequence of decreased viral load in DRG and reduced expression of pain-related genes in SC.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Antivirales/administración & dosificación , Herpes Simple/tratamiento farmacológico , Neuralgia Posherpética/tratamiento farmacológico , Oxadiazoles/administración & dosificación , Dolor Agudo/inmunología , Dolor Agudo/virología , Administración Oral , Animales , Modelos Animales de Enfermedad , Femenino , Herpes Simple/complicaciones , Herpes Simple/inmunología , Herpes Simple/virología , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/aislamiento & purificación , Humanos , Ratones , Neuralgia Posherpética/inmunología , Neuralgia Posherpética/virología , Carga Viral/efectos de los fármacos , Carga Viral/inmunologíaRESUMEN
Chronic inflammatory pain is a major health problem worldwide with high prevalence in women. Cerebrolysin is a multimodal neuropeptide preparation that crosses the blood brain barrier and displays neuroprotective properties in aging and disease. Previously, we showed that cerebrolysin reduced mechanical allodynia in a model of persistent inflammation and pain. We aim to build upon the findings of our previous study by investigating the response to acute administration of cerebrolysin in two models of peripheral inflammation and assessing sex differences. We utilized the complete Freund's adjuvant (CFA) that produces maximal oedema and mechanical allodynia within days and carrageenan that produces similar effects within hours. Cerebrolysin reversed the mechanical allodynia in both sexes in CFA-treated rats. On the other hand, in rats treated with carrageenan, cerebrolysin was only effective in reducing mechanical allodynia in female rats. In conclusion, the present study shows that cerebrolysin effects may be sex-specific depending on different mechanisms that are at play in these two models of peripheral inflammatory pain. Further investigations are required to determine the factors contributing to sex differences.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Aminoácidos/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Edema/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Caracteres Sexuales , Dolor Agudo/inmunología , Animales , Carragenina , Dolor Crónico/inmunología , Modelos Animales de Enfermedad , Edema/inmunología , Femenino , Adyuvante de Freund , Hiperalgesia/inmunología , Inflamación , Masculino , Dimensión del Dolor , Ratas Wistar , Factores de TiempoAsunto(s)
Dolor Agudo , Artralgia , Artritis Reumatoide , Dolor Crónico , Citocinas/sangre , Emociones/fisiología , Hidrocortisona/sangre , Inflamación , Dolor Agudo/sangre , Dolor Agudo/inmunología , Dolor Agudo/fisiopatología , Adulto , Anciano , Artralgia/sangre , Artralgia/inmunología , Artralgia/fisiopatología , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Artritis Reumatoide/fisiopatología , Dolor Crónico/sangre , Dolor Crónico/inmunología , Dolor Crónico/fisiopatología , Método Doble Ciego , Femenino , Humanos , Inflamación/sangre , Inflamación/inmunología , Inflamación/fisiopatología , Persona de Mediana EdadRESUMEN
Rutin, naturally occurring flavonoid, has reported to cover interesting multiple pharmacological properties. This study evaluated rutin or/and meloxicam effects in paw inflammation induced by formalin in mice. Mice were divided into four groups: I-Formalin group, II-Rutin 60 mg/kg (p.o.), III-Meloxicam 10 mg/kg (p.o.), plus IV-Combined rutin and meloxicam. Therapies were administered once a day for 7 days. The curative effects were assessed on inflammatory, oxidative stress, and apoptosis. Both rutin and/or meloxicam induced marked improvement in paw licking time on the 1st day and by combined treatment only on the 3rd day as well reduction in paw edema% on the 3rd day. Moreover, noticeable progress in liver malondialdehyde content, superoxide dismutase, and sorbitol dehydrogenase activities as well decline in paw interleukin-1ß level and extent of apoptosis. The results spot light on the good influence of combined rutin and meloxicam in formalin-induced mice paw inflammation to a better extent than either rutin or meloxicam lonely.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Celulitis (Flemón)/tratamiento farmacológico , Tejido Conectivo/efectos de los fármacos , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Rutina/uso terapéutico , Tiazinas/uso terapéutico , Tiazoles/uso terapéutico , Dolor Agudo/etiología , Dolor Agudo/inmunología , Dolor Agudo/prevención & control , Analgésicos no Narcóticos/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antioxidantes/efectos adversos , Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Celulitis (Flemón)/metabolismo , Celulitis (Flemón)/patología , Celulitis (Flemón)/fisiopatología , Tejido Conectivo/inmunología , Tejido Conectivo/metabolismo , Tejido Conectivo/patología , Quimioterapia Combinada , Edema/etiología , Edema/inmunología , Edema/prevención & control , L-Iditol 2-Deshidrogenasa/metabolismo , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Masculino , Meloxicam , Ratones , Tamaño de los Órganos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Distribución Aleatoria , Rutina/efectos adversos , Superóxido Dismutasa/metabolismo , Tiazinas/efectos adversos , Tiazoles/efectos adversosRESUMEN
Chronic pain is a major debilitating condition that is difficult to treat. Although chronic pain may appear to be a disorder of the nervous system, crucial roles for immune cells and their mediators have been identified as important contributors in various types of pain. This review focuses on how the immune system regulates pain and discusses the emerging roles of immune cells in the initiation or maintenance of chronic pain. We highlight which immune cells infiltrate damaged nerves, the dorsal root ganglia, spinal cord and tissues around free nerve endings and discuss through which mechanisms they control pain. Finally we discuss emerging roles of the immune system in resolving pain and how the immune system contributes to the transition from acute to chronic pain. We propose that targeting some of these immune processes may provide novel therapeutic opportunities for the treatment of chronic pain.
Asunto(s)
Dolor Agudo/inmunología , Dolor Crónico/inmunología , Sistema Inmunológico/fisiología , Inmunidad Celular , Ganglios Espinales/inmunología , Humanos , Médula Espinal/inmunologíaRESUMEN
INTRODUCTION: IL-33 signals through ST2 receptor and promotes inflammation by activating downstream pathways culminating in the production of pro-inflammatory mediators such as IL-1ß, TNF-α, and IL-6 in an NF-κB-dependent manner. In fact, compelling evidence has demonstrated the importance of IL-33/ST2 in both innate and adaptive immune responses in diseases presenting pain as an important clinical symptom. Areas covered: IL-33 is a pleiotropic cytokine with varied immune functions. Dysregulation of this pathway has been described as a key step in varied immune responses. Further, IL-33 contributes to peripheral and spinal cord nociceptor neuron sensitization in innate and adaptive inflammatory immune responses as well as in neuropathic and cancer pain. In this sense, targeting IL-33/ST2 signaling is a promising therapeutic approach. Expert opinion: The modulation of IL-33/ST2 signaling represents a possible approach in regulating immune functions. In addition to immune function, strategies targeting IL-33/ST2 signaling pathway display a favorable preclinical analgesic profile in both acute and chronic models of pain. Therefore, IL-33-targeting therapies represent a potential target for the development of novel analgesic drugs given that IL-33 activates, for instance, neutrophils, mast cells, macrophages, astrocytes, and microglia that are important cells in the induction and maintenance of chronic pain states.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Dolor Crónico/tratamiento farmacológico , Interleucina-33/metabolismo , Dolor Agudo/inmunología , Analgésicos/farmacología , Animales , Dolor Crónico/inmunología , Citocinas/inmunología , Diseño de Fármacos , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/inmunología , Terapia Molecular Dirigida , Transducción de Señal/efectos de los fármacosRESUMEN
This article reports the case of a 45-year-old male immunocompetent patient who presented with acute epigastric pain and vomiting. Diagnostic tests confirmed a recent cytomegalovirus (CMV) infection as a contributory cause of a florid gastric ulcer. Primary CMV infections affecting the upper gastrointestinal tract are rare in immunocompetent adults. In this case treatment with a proton pump inhibitor and eradication of concomitant Helicobacter pylori colonization led to a full recovery. Anti-CMV treatment was not necessary.
Asunto(s)
Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/inmunología , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/inmunología , Huésped Inmunocomprometido/inmunología , Úlcera Gástrica/inmunología , Úlcera Gástrica/prevención & control , Dolor Abdominal/diagnóstico , Dolor Abdominal/inmunología , Dolor Abdominal/prevención & control , Dolor Agudo/diagnóstico , Dolor Agudo/inmunología , Dolor Agudo/prevención & control , Antibacterianos/administración & dosificación , Antivirales/administración & dosificación , Infecciones por Citomegalovirus/diagnóstico , Diagnóstico Diferencial , Gastritis/diagnóstico , Gastritis/tratamiento farmacológico , Gastritis/inmunología , Infecciones por Helicobacter/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Bomba de Protones/uso terapéutico , Úlcera Gástrica/diagnóstico , Vómitos/diagnóstico , Vómitos/inmunología , Vómitos/prevención & controlRESUMEN
PURPOSE OF REVIEW: The current review provides a summary of recent advances in our understanding of the neuroimmune interactions which influence the development of pain associated with cancer. RECENT FINDINGS: Common signalling pathways, mediators and immune cell types are involved in the generation of pain as a result of both cancer and its treatment. Distinct alterations in central and peripheral neuronal function occur in multiple forms of cancer pain. Other more unusual neuroimmune processes such as graft-versus-host disease may cause cancer pain. SUMMARY: Identification of the cellular processes which underlie the generation of cancer pain provide potential novel targets for drug development and may eventually lead to improved pain management for cancer patients.
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Antineoplásicos/efectos adversos , Neoplasias Óseas/fisiopatología , Enfermedad Injerto contra Huésped/fisiopatología , Inmunidad Celular/fisiología , Neoplasias/fisiopatología , Neuralgia/inmunología , Neuroinmunomodulación/fisiología , Dolor Agudo/etiología , Dolor Agudo/inmunología , Dolor Agudo/fisiopatología , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Neoplasias Óseas/inmunología , Neoplasias Óseas/secundario , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Humanos , Inmunidad Celular/efectos de los fármacos , Neoplasias/inmunología , Neoplasias/terapia , Neuralgia/inducido químicamente , Neuralgia/etiología , Dolor Postoperatorio/etiología , Dolor Postoperatorio/inmunología , Dolor Postoperatorio/fisiopatología , Sistema Nervioso Periférico/inmunología , Sistema Nervioso Periférico/fisiopatología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Transducción de Señal/fisiologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The infusion or decoction of Mirabilis jalapa leaves is used in traditional medicine in Brazil to treat inflammatory and painful diseases. Thus, the present study was designed to investigate whether the leaf ethyl acetate (Eta) fraction from Mirabilis jalapa exhibits antinociceptive effect in clinically relevant pain models in mice. Furthermore, we have investigated the role of cholinergic system in the antinociceptive action produced by Eta in mice. MATERIALS AND METHODS: The effect of Eta administered orally (10mg/kg, p.o.) in mice was verified on the painful hypersensitivity (mechanical allodynia) in models of chronic inflammation (subcutaneous injection of complete Freund's Adjuvant-CFA in the plantar surface of the right hind paw), postoperative (paw surgical incision) and neuropathic (partial sciatic nerve ligation) pain. In the chronic inflammation model, we further verified the effect of Eta treatment on paw edema and interleukin-1ß (IL-1ß) levels. We also investigated the role of muscarinic and nicotinic receptors in the antiallodynic action produced by Eta as well as the possible action of Eta on in vitro and ex vivo acetylcholinesterase activity in CFA treated animals. Furthermore, we verified the effect of Eta treatment on the parameters of liver and kidney lesion (level of urea, and activity of aspartate aminotransferase and alanine aminotransferase). RESULTS: Eta produced marked reduction in the allodynia caused by CFA, surgical incision and partial sciatic nerve ligation. However, Eta did not alter the paw edema or the increase of IL-1ß levels produced by CFA. The antinociceptive effect of Eta was reversed by the pre-treatment of animals with the antagonists of muscarinic (atropine, 5mg/kg, s.c) or nicotinic (mecamylamine, 0.001mg/kg, s.c.) receptors. Eta did not alter in vitro acetylcholinesterase activity in blood or spinal cord samples, but it reversed the increase in the acetylcholinesterase activity observed in the spinal cord samples from mice injected with CFA. Moreover, Eta did not alter the indicators of liver or kidney lesion. CONCLUSIONS: Based on its use in traditional medicine, the results of the present study confirmed the antinociceptive properties of Eta in clinically relevant pain models. Also its effect on the CFA-induced chronic inflammation seems to be related to acetylcholinesterase inhibition and cholinergic system.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Analgésicos/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Acetilcolinesterasa/metabolismo , Dolor Agudo/enzimología , Dolor Agudo/inmunología , Analgésicos/aislamiento & purificación , Analgésicos/toxicidad , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/enzimología , Artritis Experimental/inmunología , Dolor Crónico/enzimología , Dolor Crónico/inmunología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/enzimología , Hiperalgesia/inmunología , Interleucina-1beta/inmunología , Masculino , Ratones , Dimensión del Dolor , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/enzimología , Dolor Postoperatorio/inmunología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Hojas de la Planta/química , Neuropatía Ciática/tratamiento farmacológico , Neuropatía Ciática/enzimología , Neuropatía Ciática/inmunologíaRESUMEN
Band 3 oligomers, precociously formed in the membrane of sickle red blood cells (SS RBC) as a result of oxidative damage, induce two significant changes: (1) contribution to the adhesive nature of these cells to endothelial cells; (2) production of recognition sites for natural antiband 3 antibodies (antiband 3 Nabs). The inhibition of the adhesion of SS RBC to endothelial cells by band 3 peptides suggests a participation of antiband 3 Nabs in the etiology and prevention of vaso-occlusive crises (VOC). To address this question, we measured the levels of antiband 3 Nabs in sickle cell anaemia (SCA) patients (45 in steady state, 35 in VOC) and in controls (27 sickle trait, 30 normal AA subjects). A significant decreased of antiband 3 Nabs in the VOC group was demonstrated as compared with the steady state group, the sickle trait and healthy controls. This study provides data suggesting that Antiband 3 Nabs are likely to play a role in the SCA VOC.
Asunto(s)
Anemia de Células Falciformes/inmunología , Proteína 1 de Intercambio de Anión de Eritrocito/inmunología , Autoanticuerpos/inmunología , Dolor Agudo/sangre , Dolor Agudo/etiología , Dolor Agudo/inmunología , Adolescente , Adulto , Anemia de Células Falciformes/complicaciones , Autoanticuerpos/sangre , Adhesión Celular , Endotelio Vascular/patología , Agregación Eritrocitaria , Femenino , Humanos , Inmunidad Innata , Isquemia/sangre , Isquemia/etiología , Isquemia/inmunología , Masculino , Estrés Oxidativo , Adulto JovenAsunto(s)
Dolor Agudo/inmunología , Dolor Agudo/metabolismo , Apatitas/metabolismo , Fascitis Plantar/inmunología , Fascitis Plantar/metabolismo , Talón/diagnóstico por imagen , Dolor Agudo/diagnóstico por imagen , Fascia/diagnóstico por imagen , Fascia/inmunología , Fascia/metabolismo , Fascitis Plantar/diagnóstico por imagen , Femenino , Humanos , Persona de Mediana Edad , RadiografíaRESUMEN
Tetrodotoxin (TTX) is a potent neurotoxin that blocks voltage-gated sodium channels (VGSCs). VGSCs play a critical role in neuronal function under both physiological and pathological conditions. TTX has been extensively used to functionally characterize VGSCs, which can be classified as TTX-sensitive or TTX-resistant channels according to their sensitivity to this toxin. Alterations in the expression and/or function of some specific TTX-sensitive VGSCs have been implicated in a number of chronic pain conditions. The administration of TTX at doses below those that interfere with the generation and conduction of action potentials in normal (non-injured) nerves has been used in humans and experimental animals under different pain conditions. These data indicate a role for TTX as a potential therapeutic agent for pain. This review focuses on the preclinical and clinical evidence supporting a potential analgesic role for TTX. In addition, the contribution of specific TTX-sensitive VGSCs to pain is reviewed.
Asunto(s)
Analgésicos no Narcóticos/uso terapéutico , Neurotoxinas/uso terapéutico , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/metabolismo , Tetrodotoxina/uso terapéutico , Dolor Agudo/tratamiento farmacológico , Dolor Agudo/inmunología , Dolor Agudo/metabolismo , Animales , Humanos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/inmunología , Neuralgia/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Canales de Sodio/química , Canales de Sodio/genéticaRESUMEN
Growing evidence suggests that systemic immune activation plays a role in the pathophysiology of pain in functional bowel disorders. By implementing a randomized crossover study with an injection of endotoxin or saline, we aimed to test the hypothesis that endotoxin-induced systemic inflammation increases visceral pain sensitivity in humans. Eleven healthy men (mean ± standard error of the mean age 26.6 ± 1.1 years) received an intravenous injection of either lipopolysaccharide (LPS; 0.4 ng/kg) or saline on 2 otherwise identical study days. Blood samples were collected 15 min before and 1, 2, 3, 4, and 6h after injection to characterize changes in immune parameters including proinflammatory cytokines. Rectal sensory and pain thresholds and subjective pain ratings were assessed with barostat rectal distensions 2h after injection. LPS administration induced an acute inflammatory response indicated by transient increases in tumor necrosis factor alpha, interleukin 6, and body temperature (all P<.001). The LPS-induced immune activation increased sensitivity to rectal distensions as reflected by significantly decreased visceral sensory and pain thresholds (both P<.05) compared to saline control. Visceral stimuli were rated as more unpleasant (P<.05) and inducing increased urge to defecate (P<.01). Pain thresholds correlated with interleukin 6 at +1h (r=0.60, P<.05) and +3h (r=0.67, P<.05) within the LPS condition. This report is novel in that it demonstrates that a transient systemic immune activation results in decreased visceral sensory and pain thresholds and altered subjective pain ratings. Our results support the relevance of inflammatory processes in the pathophysiology of visceral hyperalgesia and underscore the need for studies to further elucidate immune-to-brain communication pathways in gastrointestinal disorders.
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Dolor Agudo/diagnóstico , Endotoxemia/diagnóstico , Infecciones por Escherichia coli/diagnóstico , Dimensión del Dolor/métodos , Umbral del Dolor/fisiología , Dolor Visceral/diagnóstico , Dolor Agudo/inmunología , Dolor Agudo/fisiopatología , Adulto , Estudios Cruzados , Citocinas/sangre , Endotoxemia/sangre , Endotoxemia/inmunología , Escherichia coli , Infecciones por Escherichia coli/sangre , Infecciones por Escherichia coli/inmunología , Humanos , Lipopolisacáridos/toxicidad , Masculino , Dolor Visceral/sangre , Dolor Visceral/inmunología , Adulto JovenRESUMEN
The present study compared cortisol and soluble tumor necrosis factor-α receptor II (sTNFαRII) responses provoked by cold pressor, hot water, ischemic, and neutral water (i.e., room temperature) modalities. Oral fluid samples were collected before, immediately after, and during recovery to assess physiological responses. From baseline, the cold pressor, but not hot water or ischemic modalities, produced a significant time-dependent elevation in cortisol, whereas cortisol significantly decreased for the neutral water task. When compared to baseline, the cold pressor, hot water, and ischemic modalities were associated with decreased sTNFαRII responses over time. The sTNFαRII response to neutral water initially decreased but returned to approximate baseline levels. Pain ratings were positively associated with cortisol increase from baseline and the overall cortisol response was negatively associated with the overall sTNFαRII response.