Luciano Aguilera

Disinhibition of spinal responses to primary afferent input by antagonism at GABA receptors in urethane-anaesthetised rats is dependent on NMDA and metabotropic glutamate receptors.

Disruption of spinal GABAergic circuits, which regulate the conveyance of sensory information to spinal cord neurones from the primary afferent system, leads to miscoding of afferent input and often results in hyperresponsiveness states. In the present work, extracellular field potentials elicited by electrical peripheral nerve activation were recorded in the urethane-anaesthetised rat following spinal administration of GABA(A) or GABA(B) receptor-antagonists, and the involvement of glutamate receptors of the NMDA and metabotropic types in changes induced by altered GABAergic function was examined by pre-treating the spinal dorsal horn with appropriate antagonist drugs. Spinal administration of the GABA(A) receptor antagonist bicuculline (BIC) dose-dependently augmented poly- but not monosynaptic field potentials elicited by activation of A fibres or potentials elicited by activation of C fibres, whereas application of the GABA(B) receptor antagonist CGP35348 significantly increased the amplitudes of C- but not A fibre-evoked potentials. BIC-induced augmentation was blocked by pre-treatment with the NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) or the group I or II metabotropic glutamate receptor (mGluR)-antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) or (2S)-alpha-ethylglutamic acid (EGLU), respectively, but not by the group III mGluR-antagonist (RS)-alpha-methylserine-O-phosphate (MSOP). Augmentation of spinal field potentials induced by CGP35348 was prevented by pre-treatment with D-AP5 but not with mGluR-antagonists. The present findings provide novel evidence that disparate synaptic mechanisms subserved by metabotropic and NMDA glutamate receptors may be involved in spinal hyperresponsiveness states secondary to decreased GABA(A) or GABA(B) receptor activity.

Selective impairment of spinal mu-opioid receptor mechanism by plasticity of serotonergic facilitation mediated by 5-HT2A and 5-HT2B receptors

Summary Plasticity of serotonergic neurotransmission mediated by 5‐HT2A and 5‐HT2B receptors impairs spinal mu‐opioid of receptor efficacy during neuropathic pain, including upregulation of receptor expression in mu‐opioid receptor containing neurons. ABSTRACT Opioid analgesia is compromised by intracellular mediators such as protein kinase C (PKC). The phosphatidylinositol hydrolysis‐coupled serotonin receptor 5‐HT2 is ideally suited to promote PKC activation. We test the hypothesis that 5‐HT2A and 5‐HT2B receptors, which have been previously shown to become pro‐excitatory after spinal nerve ligation (SNL), can negatively influence the ability of opioids to depress spinal excitation evoked by noxious input. Spinal superfusion with (100 nM) mu‐opioid receptor (MOR)‐agonist DAMGO significantly depressed C fiber‐evoked spinal field potentials. Simultaneous administration of subclinical 5‐HT2AR antagonist 4F 4PP (100 nM) or 5‐HT2BR antagonist SB 204741 (100 nM) significantly reduced the IC50 value for DAMGO in nerve‐ligated rats (97.56 nM ± 1.51 and 1.20 nM ± 1.28 respectively, relative to 104 nM ± 1.08 at the baseline condition), but not in sham‐operated rats. Both antagonists failed to alter depression induced by delta‐opioid receptor (DOR)‐agonist D‐ala2‐deltorphin II after SNL as well as in the sham condition. Western blot analysis of dorsal horn homogenates revealed bilateral upregulation of 5‐HT2AR and 5‐HT2BR protein band densities after SNL. As assessed from double immunofluorescence labeling for confocal laser scanning microscopy, scarce dorsal horn cell processes showed co‐localization color overlay for 5‐HT2AR/MOR, 5‐HT2BR/MOR, 5‐HT2AR/DOR, or 5‐HT2BR/DOR in sham‐operated rats. Intensity correlation‐based analyses showed significant increases in 5‐HT2AR/MOR and 5‐HT2BR/MOR co‐localizations after SNL. These results indicate that plasticity of spinal serotonergic neurotransmission can selectively reduce spinal MOR mechanisms via 5‐HT2A and 5‐HT2B receptors, including upregulation of the latter and increased expression in dorsal horn neurons containing MOR.

Morphine‐induced depression of spinal excitation is not altered following acute disruption of GABAA or GABAB receptor activity

Loss of spinal inhibitory mechanisms is thought to contribute to the pathophysiology of abnormal pain states, including neuropathic pain. By using an evoked spinal field potential technique, the hypothesis was tested here that decreased spinal GABAergic control underlies poor response to morphine (MOR) that often accompanies neuropathic pain. Therefore, field potentials evoked by electrical peripheral nerve stimulation during spinal superfusion with MOR were recorded in rats rendered neuropathic by a spinal nerve ligation (SNL) procedure, and compared to responses recorded in naïve rats. MOR effects on evoked field potentials were then assessed in rats in which spinal GABAergic inhibition had been acutely reduced by treatment with GABAA and GABAB receptor‐antagonists.

Depression of C fibre-evoked spinal field potentials by the spinal δ opioid receptor is enhanced in the spinal nerve ligation model of neuropathic pain: Involvement of the μ-subtype

The depression rate of C fibre-evoked spinal field potentials by spinally applied morphine is increased in two states of spinal hyperexcitation, namely the spinal ligation model (SNL) of neuropathic pain and long-term potentiation (LTP) of C fibre-evoked spinal field potentials. This present work sought to determine opioid receptor subtypes involved in such increase in the SNL model. We recorded spinal field potentials during spinal superfusion with increasing, cumulative concentrations of selective subtype-specific agonists in rats subjected to SNL, as well as in non-ligated animals. The mu opioid receptor (MOR) agonist DAMGO significantly depressed field potentials evoked by C (100 nM) or Adelta fibres (1 microM) both in neuropathic and non-ligated rats, whereas the kappa receptor opioid (KOR) agonist +/-U-50488 was ineffective. The delta opioid receptor (DOR) (D-Ala2)-Deltorphin II was more effective in reducing C fibre-evoked spinal field potentials in rats subjected to SNL (100 nM) than in non-ligated rats (100 microM). Subclinical MOR activation (10 nM DAMGO) produced a leftward shift in (D-Ala2)-Deltorphin II dose-response curve in non-ligated rats (IC50 16.59 +/- 0.99 microM vs 120.3 +/- 1.0 microM in the absence of DAMGO), and isobolar analysis revealed synergistic interaction (interaction index 0.25). MOR blockade (100 microM CTOP) disinhibited C fibre-evoked potentials in neuropathic, but not in basal animals, and partially impeded DOR depression in both groups. DOR blockade (1 mM naltrindole) was ineffective in either group. We show that DOR-mediated depression of spinal responses to peripheral unmyelinated fibre-input is increased in the SNL model, an increase that is contributed to by positive interaction with the spinal MOR.

Non-linear morphine-induced depression of spinal excitation following long-term potentiation of C fibre-evoked spinal field potentials

Reduced efficacy of opioid analgesics in some abnormal pain states is a common clinical observation. We tested whether the depressing effect of spinally administered morphine (MOR) on C fibre‐evoked spinal field potentials is diminished during long‐term potentiation (LTP) induced in the spinal dorsal horn by high‐frequency stimulation (HFS). MOR distinctly reduced evoked field potentials 2h after LTP induction, yet MOR doses suppressing spinal responses in control rats (500μM) failed to achieve so in HFS‐receiving rats. However, HFS and MOR administration at the 0.01–0.1mM range were found to interact positively as independent variables, suggesting that LTP induction may trigger an endogenous factor enhancing the effectiveness of spinally applied MOR.

An artificial neural network approach for predicting functional outcome in fibromyalgia syndrome after multidisciplinary pain program.

OBJECTIVE The objective of this study was to evaluate the ability of artificial neural networks (ANNs) to predict, on the basis of clinical variables, the response of persons with fibromyalgia syndrome (FMS) to a standard, 4-week interdisciplinary pain program. DESIGN The design of this study is retrospective longitudinal. SETTING Fibromyalgia outpatient clinic in a tertiary-care general hospital. SUBJECTS The subjects of this study include outpatients with FMS. INTERVENTION Multidisciplinary pain program including pain pharmacotherapy, cognitive-behavioral therapy, physical therapy, and occupational therapy. OUTCOME MEASURES Reliable change (RC) of scores on the Stanford Health Assessment Questionnaire (HAQ), and accuracy of ANNs in predicting RC at discharge or at 6-month follow-up as compared to Logistic Regression. RESULTS ANN-based models using the sensory-discriminative and affective-motivational subscales of the McGill Pain Questionnaire, the HAQ disability index, and the anxiety subscale of Hospital Anxiety and Depression Scale at baseline as input variables correctly classified 81.81% of responders at discharge and 83.33% of responders at 6-month follow-up, as well as 100% of nonresponders at either evaluation time-point. Logistic regression analysis, which was used for comparison, could predict treatment outcome with accuracies of 86.11% and 61.11% at discharge and follow-up, respectively, based on baseline scores on the HAQ and the mental summary component of the Medical Outcomes Study-Short Form 36. CONCLUSIONS Properly trained ANNs can be a useful tool for optimal treatment selection at an early stage after diagnosis, thus contributing to minimize the lag until symptom amelioration and improving tertiary prevention in patients with FMS.

516 ANXIETY, DEPRESSION AND PERCEIVED SOCIAL SUPPORT IN FIBROMYALGIA SYNDROME PATIENTS

the adult population, mainly women. Fibromyalgia is characterized by widespread musculoskeletal pain and anatomical defined tender points, but also by fatigue, morning stiffness, disturbed sleep, and cognitive disturbance. Our main goals were to assess the prevalence and associations among psychosocial variables namely, health status perception, emotional distress, negative affect, positive affect, social support, and coping with chronic pain. On the other hand, we intended to access illness representations, as well as life stories of fibromyalgia patients. A mixed methodological approach was used. The quantitative study included 128 fibromyalgia patients, 52 rheumatoid arthritis patients, and 91 healthy controls who completed a set of self-report measures. In the qualitative study 20 fibromyalgia patients were interviewed. Results have shown that fibromyalgia patients have significantly lower levels of health status perception and positive affect, as well as significantly higher levels of emotional distress, negative affect, avoidance, and worrying. Concerning to qualitative study, we have found support for the presence of predisposing, triggering, and maintenance factors in participants’ life stories. Furthermore, relating to illness representations four categories have emerged, specifically: (a) finding a diagnosis: fibromyalgia, (b) a changed life (c) coping with fibromyalgia and, (d) perspectives about a new reality. Overall, we point out the usefulness of a biopsychosocial approach on assessment and intervention on fibromyalgia patients in order to improve their quality of life.

Antiinflamatorios no esteroideos y paracetamol en el tratamiento del dolor

Los antiinflamatorios no esteroideos (AINES) y el PARACETAMOL incluye un grupo de farmacos con estructuras quimicas diferentes que forman junto a la medicacion coadyuvante el primer escalon del tratamiento del dolor propuesto por la OMS o que complementa la analgesia en los demas escalones. Estos medicamentos poseen un mecanismo de accion periferico sobre el proceso inflamatorio y tambien central minorando la transmision del impulso doloroso. Se estudia su eficacia en los diversos tipos de dolor. Se discutira la posibilidad de obtener analgesia con estos farmacos valorando las distintas familias de los mismos y sus caracteristicas farmacologicas especificas, incluyendo los nuevos inhibidores selectivos de la COX-2. Se revisan los efectos adversos de estos medicamentos en especial sus acciones en el sistema gastrointestinal, renal, cardiovascular, hepatico y hematologico, sus reacciones de hipersensibilidad y posibles interferencias medicamentosas. Por ultimo se sugiere una guia para su uso correcto.

La Sensibilización Central en la fisiopatología del dolor

Experimental and clinical evidence has shown that tissue injury may lead to Central Sensitization (CS), i.e. a reversible increase in the excitability of central nervous system (CNS) neurones which is characterised by spontaneous or persistent pain, expansion of painful areas, and qualitative sensory disturbances including allodynia and hyperalgesia. CS results from a series of functional and anatomical changes, some of which may be potentially irreversible, that may be at least partially responsible for the persistence of pain once the triggering tissue injury has healed. The severity of acute pain appears to be a key factor therein, irrespective of accompanying neuropathy. Beyond the experimental setting, CS arises as a clinically relevant mechanism in the pathophysiology of pain in a variety of common clinical conditions.

688 THE EFFECTIVENESS AND TOLERANCE OF OXYCODONE IN OPIOID SWITCHING

Introduction: The opioid switching has been proposed as being effective in the treatment of pain, improving the efficacy of the first opioid or tolerance to adverse effects. Materials and Methods: 50 patients were studied with chronic nononcological pain, receiving opioid treatment with an insufficient analgesic effect (56%), or which was intolerated, and who were subsequently rotated to oxycodone. The analgesic effect was evaluated using EVA and noting the adverse effects (dizziness, drowsiness, nausea, dry mouth and constipation). Results: Pain control (table 1)