RESUMEN
The CNS houses naturally occurring pathways that project from the brain to modulate spinal neuronal activity. The noradrenergic locus coeruleus (the A6 nucleus) originates such a descending control whose influence on pain modulation encompasses an interaction with a spinally projecting non-cerulean noradrenergic cell group. Hypothesizing the origin of an endogenous pain inhibitory pathway, our aim was to identify this cell group. A5 and A7 noradrenergic nuclei also spinally project. We probed their activity using an array of optogenetic manipulation techniques during in vivo electrophysiological experimentation. Interestingly, noxious stimulus evoked spinal neuronal firing was decreased upon opto-activation of A5 neurons (two-way ANOVA with Tukey post hoc, P < 0.0001). Hypothesizing that this may reflect activity in the noradrenergic diffuse noxious inhibitory control circuit, itself activated upon application of a conditioning stimulus, we opto-inhibited A5 neurons with concurrent conditioning stimulus application. Surprisingly, no spinal neuronal inhibition was observed; activity in the diffuse noxious inhibitory control circuit was abolished (two-way ANOVA, P < 0.0001). We propose that the A5 nucleus is a critical relay nucleus for mediation of diffuse noxious inhibitory controls. Given the plasticity of diffuse noxious inhibitory controls in disease, and its back and forward clinical translation, our data reveal a potential therapeutic target.
Asunto(s)
Control Inhibidor Nocivo Difuso , Humanos , Control Inhibidor Nocivo Difuso/fisiología , Dolor/metabolismo , Neuronas/metabolismo , Locus Coeruleus/metabolismo , Encéfalo/metabolismo , Norepinefrina/metabolismo , Médula Espinal/metabolismoRESUMEN
Diffuse noxious inhibitory control (DNIC) is a phenomenon to reflect descending pain modulation in animals. Conditioned pain modulation (CPM) is the human counterpart of DNIC and is reduced in patients with several chronic pain conditions. Duloxetine is a serotonin and noradrenaline reuptake inhibitor that ameliorates CPM impairment in patients with diabetic neuropathy. Although some studies have reported the effects of different pharmacological agents on CPM, few studies have compared the effects of some analgesics in both humans and rodents. Therefore, we established a stable evaluation method for DNIC in rats and determined whether duloxetine and other specific analgesics affect DNIC impairment in rat models of peripheral neuropathic pain and osteoarthritis pain, two types of chronic pain. As a conditioning stimulus, capsaicin was injected into the forepaw of rats. The paw withdrawal threshold (PWT) in response to mechanical pressure was measured for the hindpaw. Peripheral neuropathic pain and osteoarthritis pain models were developed by partial sciatic nerve ligation (PSNL) and the intra-articular injection of 2â¯mg monoiodoacetate (MIA), respectively. Capsaicin (30-100⯵g/site) increased the PWT, in a dose-dependent manner, in naive rats. The threshold significantly increased at 30⯵g and reached its maximal level at 100⯵g. The change in PWT following capsaicin injection was significantly reduced in PSNL-treated rats, but the threshold was increased by the subcutaneous administration of duloxetine (10â¯mg/kg). The oral administrations of pregabalin (10â¯mg/kg) and celecoxib (3â¯mg/kg) did not affect the PWT in PSNL-treated rats. Similarly, MIA-injected rats also showed a reduced change in PWT following capsaicin injection. Duloxetine, but not pregabalin and celecoxib, significantly increased the PWT in MIA-injected rats. These results suggested that duloxetine can directly ameliorate DNIC impairment in rat models of chronic pain. Duloxetine may be useful for modulating chronic pain by restoring function to the endogenous, descending, inhibitory pathway.
Asunto(s)
Analgésicos/farmacología , Dolor Crónico/tratamiento farmacológico , Control Inhibidor Nocivo Difuso/efectos de los fármacos , Clorhidrato de Duloxetina/farmacología , Osteoartritis de la Rodilla/tratamiento farmacológico , Animales , Control Inhibidor Nocivo Difuso/fisiología , Masculino , Neuralgia/tratamiento farmacológico , Neuralgia/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Pregabalina/farmacología , Ratas Sprague-DawleyRESUMEN
The diffuse noxious inhibitory control, which has been investigated extensively in animals, consists of the inhibitory modulation of pain pathways after heterotopic noxious stimulation. The subnucleus reticularis dorsalis, which lies in the caudal part of the medulla, together with its descending projections to the wide-dynamic-range neurones, is responsible for the diffuse noxious inhibitory control. Many studies have investigated the diffuse noxious inhibitory control phenomenon in humans. However, owing to the complexity of the effect of descending modulation on human pain perception, expert opinion has recommended the term "conditioned pain modulation" to describe the psychophysical paradigm in which a heterotopic noxious stimulus is used to affect pain pathways in humans. In this narrative review, we present the current knowledge on the mechanisms underlying the diffuse noxious inhibitory control in animals and show how this phenomenon can be investigated in humans by using the conditioned pain modulation paradigm. We also demonstrate the relevance of conditioned pain modulation to the pathophysiology of pain.
Asunto(s)
Control Inhibidor Nocivo Difuso/fisiología , Percepción del Dolor/fisiología , Dolor/fisiopatología , Animales , HumanosRESUMEN
Phasic pain stimuli are inhibited when they are applied concomitantly with a conditioning tonic stimulus at another body location (heterotopic noxious conditioning stimulation, HNCS). While the effects of HNCS are thought to rely on a spino-bulbo-spinal mechanism in animals (termed diffuse noxious inhibitory controls, DNIC), the underlying neurophysiology in humans may involve other pathways. In this study, we investigated the role of concomitant supraspinal mechanisms during HNCS by presenting auditory stimuli during a conditioning tonic painful stimulus (the cold pressor test, CPT). Considering that auditory stimuli are not conveyed through the spinal cord, any changes in brain responses to auditory stimuli during HNCS can be ascribed entirely to supraspinal mechanisms. Electroencephalography (EEG) was recorded during HNCS, and auditory stimuli were administered in three blocks, before, during and after HNCS. Nociceptive withdrawal reflexes (NWRs) were recorded at the same time points to investigate spinal processing. Our results showed that AEPs were significantly reduced during HNCS. Moreover, the amplitude of the NWR was significantly diminished during HNCS in most participants. Given that spinal and supraspinal mechanisms operate concomitantly during HNCS, the possibility of isolating their individual contributions in humans is questionable. We conclude that the net effects of HCNS are not independent from attentional/cognitive influences.
Asunto(s)
Inhibición Neural/fisiología , Dolor/psicología , Reflejo/fisiología , Médula Espinal/fisiopatología , Adulto , Condicionamiento Clásico/fisiología , Control Inhibidor Nocivo Difuso/fisiología , Femenino , Humanos , Masculino , Dolor/fisiopatología , Estimulación Física , Médula Espinal/fisiología , Adulto JovenRESUMEN
BACKGROUND: Many Osteoarthritis (OA) patients report with clinical features to their pain that cannot be explained by purely peripheral mechanisms. Yet, the analgesic agents available that tackle centrally driven chronic pain often provide only partial pain relief, or have dose-limiting side effects. We explored a combination therapy of the centrally acting analgesic agents tapentadol and pregabalin, to investigate if they could be used in combination to provide superior analgesia. METHODS: Using electrophysiological single-unit recordings taken from spinal wide dynamic range neurons, Diffuse Noxious Inhibitory Controls (DNIC) were assessed as a marker of potential changes in descending controls in a monoiodoacetate (MIA) model of OA. We investigated if a subcutaneous injection of tapentadol or pregabalin, both alone and in combination, inhibited neuronal responses and restored the expression of DNIC, quantified as a reduction in neuronal firing in the presence of a conditioning noxious stimulus. RESULTS: Tapentadol restored DNIC-induced neuronal inhibition in MIA animals, while pregabalin inhibited pre-conditioned mechanically evoked neuronal responses but did not restore DNIC. Given in combination, tapentadol and pregabalin restored DNIC expression and also inhibited spinal neuronal responses. CONCLUSIONS: We propose that there is both central sensitization and an imbalance in inhibitory and facilitatory descending controls in MIA animals. The combination therapy of tapentadol and pregabalin restored descending noradrenergic inhibitory tone and also inhibited nociceptive transmission at the level of the spinal cord. SIGNIFICANCE: This study shows that pregabalin and tapentadol target different mechanisms of centrally driven chronic pain associated with osteoarthritis, and that when administered together can restore descending inhibitory tone whilst also tackling spinal neuronal hyperexcitability and may therefore provide superior analgesia.
Asunto(s)
Osteoartritis/tratamiento farmacológico , Pregabalina/farmacología , Tapentadol/farmacología , Analgesia , Analgésicos/uso terapéutico , Animales , Dolor Crónico/tratamiento farmacológico , Control Inhibidor Nocivo Difuso/fisiología , Humanos , Masculino , Neuronas/efectos de los fármacos , Norepinefrina , Médula Espinal/metabolismoRESUMEN
Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate (MIA) model of OA. Particularly, this study explores the functionality of descending controls over the course of the model by assessing diffuse noxious inhibitory controls (DNIC). Early-phase MIA animals have a functional DNIC system, whereas DNIC are abolished in late-phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early-phase animals, blocking the actions of spinal α2-adrenergic receptors completely abolishes DNIC, whereas blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal α2-adrenergic or 5-HT7 receptors in late-phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. NEW & NOTEWORTHY This study showed that there are both noradrenergic and serotonergic components contributing to the expression of diffuse noxious inhibitory controls (DNIC). Furthermore, although a tonic descending noradrenergic tone is always crucial for the expression of DNIC, variations in descending serotonergic signaling over the course of the model mean this component plays a more vital role in states of sensitization.
Asunto(s)
Control Inhibidor Nocivo Difuso/fisiología , Osteoartritis/metabolismo , Osteoartritis/terapia , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Serotonina/metabolismo , Médula Espinal/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Animales , Control Inhibidor Nocivo Difuso/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ácido Yodoacético , Masculino , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Norepinefrina/metabolismo , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Médula Espinal/efectos de los fármacosRESUMEN
Diffuse noxious inhibitory control (DNIC), which involves endogenous pain modulation, has been investigated as a potential mechanism for the differences in pain modulation observed between men and women, though the literature shows contradictory findings. We used a capsaicin-induced DNIC behavioral assay and resting state functional magnetic resonance imaging (rsfMRI) to assess the effect of testosterone on pain modulation and related brain circuitry in rats. We hypothesized that testosterone is required for DNIC that leads to efficient pain inhibition by increasing descending pain modulation. Male, female, and orchidectomized (GDX) male rats had a capsaicin injection into the forepaw to induce DNIC and mechanical thresholds were observed on the hindpaw. rsfMRI scans were acquired before and after capsaicin injection to analyze the effects of DNIC on periaqueductal gray (PAG), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) connectivity to the whole brain. The strength of DNIC was higher in males compared to females and GDX males. PAG connectivity with prelimbic cortex (PrL), ACC and insula was stronger in males compared to females and GDX males, whereas females and GDX males had increased connectivity between the right ACC, hippocampus and thalamus. GDX males also showed a stronger connectivity between right ACC and NAc, and right NAc with PrL, ACC, insula and thalamus. Our findings suggest that testosterone plays a key role in reinforcing the endogenous pain inhibitory system, while circuitries related to reward and emotion are more strongly recruited in the absence of testosterone.
Asunto(s)
Encéfalo/metabolismo , Control Inhibidor Nocivo Difuso/fisiología , Testosterona/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Femenino , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/metabolismo , Orquiectomía , Ratas Sprague-Dawley , Descanso , Caracteres SexualesRESUMEN
The aim of the present study was to compare the effects of explicit suggestions of analgesia and of the activation of the Diffuse Noxious Inhibitory Control (DNIC) by cold pressor test on pain perception and heart rate in healthy participants with high (highs, N=18), low (lows, N=18) and intermediate scores of hypnotizability (mediums, N=15) out of hypnosis. Pain reports and the stimulus-locked heart rate changes induced by electrical nociceptive stimulation of the left hand were studied in the absence of concomitant stimuli (Control), during suggestions of analgesia (SUGG, glove analgesia) and during cold pressor test used as a conditioning stimulus to the right hand (DNIC, water temperature=10-12°C) in the REAL session. Participants were submitted also to a SHAM session in which the DNIC water temperature was 30°C and the suggestions for analgesia were substituted with weather forecast information. Both suggestions and DNIC reduced pain significantly in all subjects; however, the percentage of reduction was significantly larger in highs (pain intensity=55% of the control condition) than in mediums (70%) and lows (80%) independently of the REAL/SHAM session and of the specific pain manipulation. Heart rate was not modulated consistently with pain experience. Findings indicate that both suggestions and DNIC influence pain experience as a function of hypnotizability and suggest that both sensory and cognitive mechanisms co-operate in DNIC induced analgesia.
Asunto(s)
Analgesia/psicología , Control Inhibidor Nocivo Difuso/fisiología , Hipnosis/métodos , Manejo del Dolor , Dolor/psicología , Adulto , Frío , Femenino , Voluntarios Sanos , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Dolor/fisiopatología , Dimensión del Dolor , Estimulación Física/efectos adversos , Psicofísica , Estadísticas no Paramétricas , Adulto JovenRESUMEN
BACKGROUND: Following neuropathy α2-adrenoceptor-mediated diffuse noxious inhibitory controls (DNIC), whereby a noxious conditioning stimulus inhibits the activity of spinal wide dynamic range (WDR) neurons, are abolished, and spinal 5-HT7 receptor densities are increased. Here, we manipulate spinal 5-HT content in spinal nerve ligated (SNL) animals and investigate which 5-HT receptor mediated actions predominate. METHODS: Using in vivo electrophysiology we recorded WDR neuronal responses to von frey filaments applied to the hind paw before, and concurrent to, a noxious ear pinch (the conditioning stimulus) in isoflurane-anaesthetised rats. The expression of DNIC was quantified as a reduction in WDR neuronal firing in the presence of conditioning stimulus and was investigated in SNL rats following spinal application of (1) selective serotonin reuptake inhibitors (SSRIs) citalopram or fluoxetine, or dual application of (2) SSRI plus 5-HT7 receptor antagonist SB269970, or (3) SSRI plus α2 adrenoceptor antagonist atipamezole. RESULTS: DNIC were revealed in SNL animals following spinal application of SSRI, but this effect was abolished upon joint application of SSRI plus SB269970 or atipamezole. CONCLUSIONS: We propose that in SNL animals the inhibitory actions (quantified as the presence of DNIC) of excess spinal 5-HT (presumed present following application of SSRI) were mediated via 5-HT7 receptors. The anti-nociception depends upon an underlying tonic noradrenergic inhibitory tone via the α2-adrenoceptor. SIGNIFICANCE: Following neuropathy enhanced spinal serotonin availability switches the predominant spinal 5-HT receptor-mediated actions but also alters noradrenergic signalling. We highlight the therapeutic complexity of SSRIs and monoamine modulators for the treatment of neuropathic pain.
Asunto(s)
Control Inhibidor Nocivo Difuso/fisiología , Neuralgia/fisiopatología , Serotonina/fisiología , Animales , Control Inhibidor Nocivo Difuso/efectos de los fármacos , Fluoxetina/farmacología , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Fenoles/farmacología , Prilocaína/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina , Antagonistas de la Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiopatología , Nervios Espinales/efectos de los fármacos , Nervios Espinales/fisiopatología , Sulfonamidas/farmacologíaRESUMEN
Heterotopic noxious counter-stimulation (HNCS) inhibits pain and pain processes through cerebral and cerebrospinal mechanisms. However, it is unclear whether HNCS inhibits non-nociceptive processes, which needs to be clarified for a better understanding of HNCS analgesia. The aim of this study was to examine the effects of HNCS on perception and scalp somatosensory evoked potentials (SEPs). Seventeen healthy volunteers participated in two counter-balanced sessions, including non-nociceptive (selective Aß-fibre activation) or nociceptive electrical stimulation, combined with HNCS. HNCS was produced by a 20-min cold pressor test (left hand) adjusted individually to produce moderate pain (mean ± SEM: 42.5 ± 5.3 on a 0-100 scale, where 0 is no pain and 100 the worst pain imaginable). Non-nociceptive electrical stimulation was adjusted individually at 80% of pain threshold and produced a tactile sensation in every subject. Nociceptive electrical stimulation was adjusted individually at 120% of RIII-reflex threshold and produced moderate pain (45.3 ± 4.5). Shock sensation was significantly decreased by HNCS compared with baseline for non-nociceptive (P < 0.001) and nociceptive (P < 0.001) stimulation. SEP peak-to-peak amplitude at Cz was significantly decreased by HNCS for non-nociceptive (P < 0.01) and nociceptive (P < 0.05) stimulation. These results indicate that perception and brain activity related to Aß-fibre activation are inhibited by HNCS. The mechanisms of this effect remain to be investigated to clarify whether it involves inhibition of spinal wide-dynamic-range neurons by diffuse noxious inhibitory controls, supraspinal processes or both.
Asunto(s)
Encéfalo/fisiología , Control Inhibidor Nocivo Difuso/fisiología , Potenciales Evocados Somatosensoriales , Fibras Nerviosas/fisiología , Dolor Nociceptivo/fisiopatología , Percepción del Dolor , Adulto , Femenino , Humanos , MasculinoRESUMEN
Diffuse noxious inhibitory controls (DNICs) utilize descending inhibitory controls through poorly understood brain stem pathways. The human counterpart, conditioned pain modulation, is reduced in patients with neuropathy aligned with animal data showing a loss of descending inhibitory noradrenaline controls together with a gain of 5-HT3 receptor-mediated facilitations after neuropathy. We investigated the pharmacological basis of DNIC and whether it can be restored after neuropathy. Deep dorsal horn neurons were activated by von Frey filaments applied to the hind paw, and DNIC was induced by a pinch applied to the ear in isoflurane-anaesthetized animals. Spinal nerve ligation was the model of neuropathy. Diffuse noxious inhibitory control was present in control rats but abolished after neuropathy. α2 adrenoceptor mechanisms underlie DNIC because the antagonists, yohimbine and atipamezole, markedly attenuated this descending inhibition. We restored DNIC in spinal nerve ligated animals by blocking 5-HT3 descending facilitations with the antagonist ondansetron or by enhancing norepinephrine modulation through the use of reboxetine (a norepinephrine reuptake inhibitor, NRI) or tapentadol (µ-opioid receptor agonist and NRI). Additionally, ondansetron enhanced DNIC in normal animals. Diffuse noxious inhibitory controls are reduced after peripheral nerve injury illustrating the central impact of neuropathy, leading to an imbalance in descending excitations and inhibitions. Underlying noradrenergic mechanisms explain the relationship between conditioned pain modulation and the use of tapentadol and duloxetine (a serotonin, NRI) in patients. We suggest that pharmacological strategies through manipulation of the monoamine system could be used to enhance DNIC in patients by blocking descending facilitations with ondansetron or enhancing norepinephrine inhibitions, so possibly reducing chronic pain.
Asunto(s)
Monoaminas Biogénicas/antagonistas & inhibidores , Monoaminas Biogénicas/metabolismo , Control Inhibidor Nocivo Difuso/fisiología , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/terapia , Potenciales de Acción/efectos de los fármacos , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Clorhidrato de Duloxetina/uso terapéutico , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Masculino , Neuronas/efectos de los fármacos , Ondansetrón/uso terapéutico , Traumatismos de los Nervios Periféricos/patología , Traumatismos de los Nervios Periféricos/fisiopatología , Fenoles/uso terapéutico , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Antagonistas de la Serotonina/uso terapéutico , Inhibidores de Captación de Serotonina y Norepinefrina/uso terapéutico , Tapentadol , Factores de Tiempo , Yohimbina/uso terapéuticoRESUMEN
BACKGROUND: Conditioned pain modulation (CPM) is a phenomenon of 'pain inhibiting pain' that is important for understanding idiopathic pain syndromes. Because the pathophysiology of posttraumatic cold intolerance is still unknown but it could involve similar mechanisms as idiopathic pain syndromes, we evaluated the functioning of the CPM system in patients with posttraumatic cold intolerance compared to healthy controls. METHODS: Fourteen healthy controls and 24 patients diagnosed with cold intolerance using the Cold Intolerance Symptom Severity questionnaire were included in the study. Of the 24 patients with cold intolerance, 11 had a nerve lesion and 13 an amputation of one or more digits. To quantify the CPM, pain threshold for mechanical pressure was measured at the affected region as a baseline measure. Then, the contralateral hand received a cold stimulus of ice water to evoke the noxious conditioning. After the cold stimulus, the pain threshold for mechanical pressure was determined again. RESULTS: The absolute and relative changes in algometer pressure (CPM effect) between pre- and post-conditioning were significantly smaller in the cold intolerance group compared to the control group (absolute p = 0.019, relative p = 0.004). The CPM effect was significantly different between the control group and the subgroups of nerve lesion (p = 0.003) and amputation patients (p = 0.011). CONCLUSIONS: In this study, we found a CPM effect after a cold stimulus in both controls and patients. A significant weaker CPM effect compared to the controls was found, as in other chronic pain conditions. The CPM system within patients with cold intolerance is altered.
Asunto(s)
Amputación Traumática/fisiopatología , Frío/efectos adversos , Control Inhibidor Nocivo Difuso/fisiología , Umbral del Dolor/fisiología , Dolor/fisiopatología , Traumatismos de los Nervios Periféricos/fisiopatología , Adaptación Fisiológica , Adulto , Amputación Traumática/complicaciones , Estudios de Casos y Controles , Femenino , Traumatismos de los Dedos/complicaciones , Traumatismos de los Dedos/fisiopatología , Dedos/inervación , Humanos , Masculino , Nervio Mediano/lesiones , Persona de Mediana Edad , Dolor/etiología , Dimensión del Dolor , Traumatismos de los Nervios Periféricos/complicaciones , Presión/efectos adversos , Nervio Radial/lesiones , Adulto JovenRESUMEN
PURPOSE: Multiple studies have demonstrated that in healthy subjects, painful stimuli applied to one part of the body inhibit pain sensation in other parts of the body, a phenomenon referred to as conditioned pain modulation. Conditioned pain modulation is related to the presence of endogenous pain control systems. Studies have demonstrated deficits in conditioned pain modulation associated inhibition in many but not all chronic pain disorders. In this study we determine whether conditioned pain modulation is altered in subjects with interstitial cystitis/bladder pain syndrome. MATERIALS AND METHODS: Female subjects with and without the diagnosis of interstitial cystitis/bladder pain syndrome were studied psychophysically using quantitative cutaneous thermal, forearm ischemia and ice water immersion tests. Conditioned pain modulation was assessed by quantifying the effects of immersion of the hand in ice water (conditioning stimulus) on threshold and tolerance of cutaneous heat pain (test stimulus) applied to the contralateral lower extremity. RESULTS: The conditioned pain modulation responses of the subjects with interstitial cystitis/bladder pain syndrome were statistically different from those of healthy control subjects for cutaneous thermal threshold and tolerance measures. Healthy control subjects demonstrated statistically significant increases in thermal pain tolerance whereas subjects with the diagnosis of interstitial cystitis/bladder pain syndrome demonstrated statistically significant reductions in thermal pain tolerance. CONCLUSIONS: An endogenous pain inhibitory system normally observed with conditioned pain modulation was altered in subjects with interstitial cystitis/bladder pain syndrome. This finding identifies interstitial cystitis/bladder pain syndrome as similar to several other chronic pain disorders such as fibromyalgia and irritable bowel syndrome, and suggests that a deficit in endogenous pain inhibitory systems may contribute to such chronic pain disorders.
Asunto(s)
Cistitis Intersticial/fisiopatología , Control Inhibidor Nocivo Difuso/fisiología , Percepción del Dolor/fisiología , Adulto , Femenino , Humanos , Persona de Mediana Edad , Dimensión del Dolor , Sensación Térmica/fisiología , Adulto JovenRESUMEN
AIMS: To test whether temporomandibular disorders (TMD) case-control differences in conditioned pain modulation (CPM) exist, using a mechanically evoked temporal summation (TS) model. METHODS: A series of 10 repetitive, mildly noxious, mechanical stimuli were applied to the fingers of 30 women with TMD, who had a primary diagnosis of masticatory myofascial pain, and 30 age-matched healthy women. The subjects rated the pain intensity caused by the 1st, 5th, and 10th stimuli in the series. To evaluate CPM, the same series of mechanical stimulations were applied with concomitant exposure of the other hand to a painfully cold water bath. Statistical inferences were based on t tests, chi-square tests, or analysis of variance (ANOVA), as appropriate. RESULTS: Pain ratings increased significantly with stimulus repetition (P < .01) and CPM significantly reduced TS of pain (P < .01). Of particular note, both groups showed very similar degrees of CPM, with no significant group difference. CONCLUSION: Painful TMD is not necessarily associated with a compromised ability to engage the endogenous analgesic system in an experimental setting.
Asunto(s)
Agnosia/fisiopatología , Control Inhibidor Nocivo Difuso/fisiología , Percepción del Dolor/fisiología , Sumación de Potenciales Postsinápticos/fisiología , Trastornos Somatosensoriales/fisiopatología , Trastornos de la Articulación Temporomandibular/etiología , Trastornos de la Articulación Temporomandibular/fisiopatología , Adulto , Análisis de Varianza , Estudios de Casos y Controles , Enfermedad Crónica , Femenino , Humanos , Persona de Mediana Edad , Umbral del Dolor , Adulto JovenRESUMEN
The current study tested the hypothesis that conditioned pain modulation is mediated by the release of endogenous opioids with a placebo-controlled (sugar pill) study of naltrexone (50 mg) in 33 healthy volunteers over two counter-balanced sessions. Pain modulation consisted of rating of heat pain (palm) during concurrent cold water immersion (foot). Compared to baseline heat pain ratings, concurrent foot immersion lowered pain intensity ratings, which suggests an inhibitory effect, was reduced with naltrexone, suggesting at least partial dependence of inhibition on endogenous opioids. An exploratory analysis revealed that individual differences in catastrophizing moderated the effects of naltrexone; endogenous opioid blockade abolished modulation in subjects lower in catastrophizing while modulation was unaffected by naltrexone among high catastrophizers. The results suggest a role of endogenous opioids in endogenous analgesia, but hint that multiple systems might contribute to conditioned pain modulation, and that these systems might be differentially activated as a function of individual differences in responses to pain.
Asunto(s)
Catastrofización/fisiopatología , Catastrofización/psicología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Control Inhibidor Nocivo Difuso/efectos de los fármacos , Control Inhibidor Nocivo Difuso/fisiología , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor/fisiopatología , Dolor/psicología , Adulto , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Individualidad , Masculino , Péptidos Opioides/fisiología , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Adulto JovenRESUMEN
Inefficient endogenous pain inhibition, in particular impaired conditioned pain modulation (CPM), may disturb central pain processing in patients with chronic whiplash-associated disorders (WAD). Previous studies revealed that abnormal central pain processing is responsible for a wide range of symptoms in patients with chronic WAD. Hence, the present study aimed at examining the functioning of descending pain inhibitory pathways, and in particular CPM, in patients with chronic WAD. Thirty-five patients with chronic WAD and 31 healthy controls were subjected to an experiment evaluating CPM. CPM was induced by an inflated occlusion cuff and evaluated by comparing temporal summation (TS) of pressure pain prior to and during cuff inflation. Temporal summation was provoked by means of 10 consecutive pressure pulses at upper and lower limb location. Pain intensity of first, fifth, and 10th pressure pulse was rated. During heterotopic noxious conditioning stimulation, TS of pressure pain was significantly depleted among healthy controls. In contrast, TS was quite similar prior to and during cuff inflation in chronic WAD, providing evidence for dysfunctional CPM in patients with chronic WAD. The present study demonstrates a lack of endogenous pain inhibitory pathways, and in particularly CPM, in patients with chronic WAD, and hence provides additional evidence for the presence of central sensitization in chronic WAD.
Asunto(s)
Dolor Crónico/fisiopatología , Control Inhibidor Nocivo Difuso/fisiología , Inhibición Neural/fisiología , Lesiones por Latigazo Cervical/fisiopatología , Actividades Cotidianas , Adulto , Sistema Nervioso Central/fisiopatología , Dolor Crónico/etiología , Dolor Crónico/terapia , Condicionamiento Psicológico/fisiología , Retroalimentación Sensorial , Femenino , Humanos , Masculino , Dimensión del Dolor , Percepción del Dolor/fisiología , Umbral del Dolor/fisiología , Presión , Calidad de Vida , Lesiones por Latigazo Cervical/complicaciones , Lesiones por Latigazo Cervical/terapiaRESUMEN
AIMS: To investigate the influence of noxious stimulation of the temporomandibular joint (TMJ) on conditioned pain modulation (CPM) and the possible influence of gender on such CPM effects in the craniofacial region of humans. METHODS: Twenty healthy men and 20 healthy women participated in two sessions. Conditioning stimulation (CS) was standardized mechanical stimulation of pericranial muscles at a pain level of 5 on a 0 to 10 visual analog scale (VAS). Intra-articular electrical stimuli were applied to the left TMJ with an intensity around VAS = 5 (painful session). No electrical stimulation was applied in the control session. Pressure pain threshold (PPT) and pressure pain tolerance threshold (PPTol) were used as responses to pressure (test) stimuli and were assessed in the right masseter muscle and left forearm before and during TMJ stimulation in addition to the CS (during, immediately after, and 10 minutes after CS). PPT and PPTol were analyzed by multilevel analysis of variance. RESULTS: The parameters were not dependent on gender, assessment site, or session, but were dependent on time (PPT, PPTol: P < .001) with session-time interactions (PPT: P < .001, PPTol: P = .002). CS triggered increases in PPT and PPTol (hypoalgesia) in both sessions and without significant differences between sessions or assessment sites during CS (painful session: 49.2 ± 3.7%, control session: 46.0 ± 3.4% for PPT and painful session: 17.7 ± 3.2%, control session: 21.4 ± 3.5% for PPTol). CONCLUSION: Acute noxious stimulation of the TMJ does not alter the magnitude of CPM effects on masseter muscle pain in either gender. It is suggested that deficiencies in CPM in persistent pain conditions are most likely more related to the duration of clinical pain than the pain per se.
Asunto(s)
Condicionamiento Psicológico/fisiología , Control Inhibidor Nocivo Difuso/fisiología , Dolor Facial/fisiopatología , Articulación Temporomandibular/fisiopatología , Adulto , Análisis de Varianza , Estimulación Eléctrica , Femenino , Antebrazo/fisiopatología , Humanos , Masculino , Músculo Masetero/fisiopatología , Dimensión del Dolor , Umbral del Dolor/fisiología , Estimulación Física , Presión , Factores Sexuales , Adulto JovenRESUMEN
OBJECTIVES: Our study is aimed to evaluate the spinal cord pain processing in Huntington's disease (HD) by testing both the temporal summation threshold (TST) of the nociceptive withdrawal reflex (NWR) and the functional activity of the diffuse noxious inhibitory control (DNIC) as form of supraspinal control of pain. METHODS: We enrolled 19 HD patients and 17 healthy controls. We measured threshold (Th), Area, TST and related psychophysical pain sensations of the NWR, at baseline and during and after activation of the DNIC by means of cold pressor test (CPT) as heterotopic noxious conditioning stimulation. RESULTS: In HD patients we found a significantly higher Th and TST as well as a lower Area when compared to controls. During the CPT, a significant inhibition of reflex and psychophysical pain responses were found in both HD patients and controls when compared to baseline, without differences between the groups in CPT results. CONCLUSIONS: Our study demonstrated an abnormal spinal cord pain processing in HD patients. Abnormalities in pain processing are not apparently linked to a dysfunctional DNIC inhibitory projection system in HD patients. SIGNIFICANCE: Our findings support the hypothesis that the striatum could play a role in pain modulation and that its atrophy could affect pain processing without change the DNIC efficiency.
Asunto(s)
Control Inhibidor Nocivo Difuso/fisiología , Enfermedad de Huntington/fisiopatología , Dolor/fisiopatología , Médula Espinal/fisiopatología , Adulto , Anciano , Cuerpo Estriado/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibición Neural/fisiología , Nociceptores/fisiología , Dimensión del Dolor , Umbral del Dolor/fisiologíaRESUMEN
OBJECTIVES: The objective of the study was to assess diffuse noxious inhibitory control (DNIC) function in women with provoked vestibulodynia (PVD) compared with healthy controls through the use of 2 different methodologies. Furthermore, the study aimed to assess whether pain characteristics correlate with DNIC in women with PVD. METHODS: Twenty-three healthy control women and 23 women diagnosed with PVD by the study gynecologist participated in the study. To assess DNIC, heat pain tolerance, determined through an ascending method of limits and temporal summation of thermal pain were used as test stimuli and a cold water bath was used as the conditioning stimulus. Participants reported on pain characteristics as potential correlates with DNIC function. RESULTS: No significant group differences were found in the number of DNIC responders per group when using heat pain tolerance or temporal summation procedures to examine DNIC. The magnitude of the DNIC response was examined for the overall groups and for positive DNIC responders only. When all participants were included in the analyses with the heat pain tolerance procedure, women with PVD displayed a higher magnitude of DNIC responding. Correlations between pain variables and DNIC responding and magnitude were nonsignificant. DISCUSSION: Results support previous findings of intact DNIC function in women with PVD, using both an ascending method of limits and a temporal summation paradigm. Pain-related variables were not correlated with DNIC function in women with PVD, perhaps this unexpected finding is due to the possibility that central processes other than DNIC, such as descending facilitation, provoke or maintain this chronic pain condition.
Asunto(s)
Control Inhibidor Nocivo Difuso/fisiología , Umbral del Dolor/fisiología , Vulvodinia/psicología , Vulvodinia/terapia , Adolescente , Adulto , Análisis de Varianza , Distribución de Chi-Cuadrado , Femenino , Calor , Humanos , Persona de Mediana Edad , Dimensión del Dolor , Estimulación Física , Estadística como Asunto , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Although many studies have investigated the effectiveness of distraction as a method of pain control, the cognitive processes by which attentional re-direction is achieved, remain unclear. In this study the role of executive functioning abilities (inhibition, task switching and working memory) in the effectiveness of distraction is investigated. We hypothesized that the effectiveness of distraction in terms of pain reduction would be larger in participants with better executive functioning abilities. Ninety-one undergraduate students first performed executive functioning tasks, and subsequently participated in a cold pressor task (CPT). Participants were randomly assigned to (1) a distraction group, in which an attention-demanding tone-detection task was performed during the CPT, or (2) a control group, in which no distraction task was performed. Participants in the distraction group reported significantly less pain during the CPT, but the pain experience was not influenced by executive functioning abilities. However, the performance on the distraction task improved with better inhibition abilities, indicating that inhibition abilities might be important in focussing on a task despite the pain.