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Reunión Científica Red de Trastornos Adictivos-CIBERSAMSalamanca 27 y 28 de septiembre de 2011O31. Chronic treatment with the opioid antagonist naltrexone favours the coupling of spinal cord µ-opioid receptors to Gα z protein subunitsA. Díaz Martínez 1,2,4 , E.M. Valdizán Ruíz 1,2,4 , F. Pilar-Cuéllar 1,2,4 , A. Lantero García 1,3,5 , R. Mostany Ibañez 1 , A.V.Villar Ramos 1,3,5 , M.L. Laorden Carrasco 3,6 , M.A. Hurlé González 1,3,51. Universidad de Cantabria, Santander.2. Instituto de Biomedicina y Biotecnología de Cantabria, Santander3. Red de Trastornos Adictivos, Instituto de Salud Carlos III4.CIBERSAM, Instituto de Salud Carlos III5. IFIMAV, Santander6. Universidad de Murcia, MurciaObjectives: Opioid receptors are predominantly coupled to pertussis toxin (PTX)-sensitive, heterotrimericGα i/Gα o proteins. Sustained receptor blockade with naltrexone is among the currently available treatments fordependence disorders. The neurochemical adaptations produced by continued opioid antagonist treatmentsremain unclear. We investigated the changes in µ-opioid receptor signalling underlying pharmacologicalsupersensitivity to the effects of agonists after sustained administration of antagonists.Methods: Rats received saline or naltrexone (120 µg/h) using osmotic minipumps. On day 7, minipumps wereremoved and the analgesic response to the µ-agonist sufentanil was tested 24 hours after saline or naltrexonewithdrawal. The autoradiographic density of µ-receptors, their interaction with Gα proteins (agonist-stimulated[ 35 S]GTPγS binding and immunoprecipitation of [ 35 S]GTPγS-labelled Gα subunits) as well as µ-opioid receptordependentinhibition of the adenylyl cyclase (AC) activity were determined in spinal cord samples.Results: Chronic naltrexone withdrawal prompted antinociceptive super-sensitivity to sufentanil associated withµ-receptor up-regulation as well as increased DAMGO-stimulated [ 35 S]GTPγS binding. Concurrently, the ability ofthe opioid agonist to inhibit AC was enhanced, but the effect became resistant to PTX. Immunoprecipitation of[ 35 S]GTPγS-labelled Gα subunits confirmed that µ-receptor coupling with PTX-resistant Gα z subunits wasfavoured. The inverse agonist effect of naltrexone on cAMP accumulation was also enhanced.Conclusions: Following chronic naltrexone, µ-opioid receptors in the spinal cord experience a transduction shiftfrom PTX-sensitive Gα o and Gα i1-2-3 to PTX-resistant Gα z proteins. Consequently, the inhibitory effect ofDAMGO on the AC/cAMP pathway is enhanced. This transduction change is responsible for an increasedpharmacological response to agonists. Such changes in μ-receptor signalling activity could constitute animportant factor in the homeostatic dysregulation of the endogenous opioid system, and may possibly account forundesirable effects in patients chronically treated with naltrexone. [Supported by: Instituto de Salud Carlos III(RTICS: RD06/001) and Ministerio de Ciencia e Innovación (SAF 2007/65451 and SAF 2007/61862)].Página 40 de 41
Reunión Científica Red de Trastornos Adictivos-CIBERSAMSalamanca 27 y 28 de septiembre de 2011O32. CHRONIC NEUROPATHIC PAIN LEADS TO UP-REGULATION OF OPIOID SYSTEM IN LOCUSCOERULEUS NEURONSM Llorca-Torralba 1 , C Alba-Delgado 1 , JA. Mico 1 , P Sánchez-Blázquez 2 , E Berrocoso 11Department of Neuroscience, School of Medicine, University of Cádiz- CIBERSAM, Spain2Instituto Cajal, CSIC- CIBERSAM, Madrid, SpainIntroduction:Opioids are widely used for acute pain management. However, their use for chronic pain (neuropathic) remains asubject of debate because the high doses required with the consequential risk of tolerance and dependence.Interestingly, it has been recently suggested that chronic pain can decrease the hedonic properties (psychologicaldependence) of opioids in the ventral tegmental area. In addition to this brain area, locus coeruleus (LC) neuronshas been widely involved, in addition to pain, in the acute and chronic action of opioids (physical dependence).Therefore, LC could be differentially regulated by opioids in chronic neuropathic conditions.Objective: We propose to study the role of mu-opioid receptors in LC neuronal activity at two different phases ofneuropathic pain: 7 days after pain induction when pain hypersensitivity is already present and after 28 dayswhen, in addition, affective disorders exist.Method: Chronic constriction injury (CCI) was performed as a neuropathic model. Behavioural, extracellularrecording and inmunohistochemistry studies were performed to study mu-opioid receptors.Results: Nerve-lesioned rats developed allodynia and hyperalgesia at 7 and 28 days after surgery. Theelectrophysiological studies did not showed any changes in CC-7d. However, the spontaneous firing activity wasincreased in CCI-28d group. Further, morphine dose-response curve was shifted to left in CCI-28d groupcompared to sham and CCI-7d. This was also accompanied by an increase in the expression of mu-opioidreceptors and a pro-depressive-like behavior.Conclusions: These findings indicate that neuropathic pain after 28 days leads to the up-regulation mu-opiodreceptors in LC. These changes coincide with the onset of affective disorders in chronic neuropathic pain.Supported by MICINN/FEDER, ISCIII, FIS PI070687, PI10/01221, PI08-0417; PS09/00332; CTS-510, CTS-4303;Cátedra-Externa-Dolor-Fundación-Grünenthal, AP2007-02397, FP7-PEOPLE-2010-RG-(268377).Página 41 de 41
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