BASIC AND CLINICAL NEUROBIOLOGY



Basic and Clinical Neurobiology

BCN

General Introduction

To write a short overview of the division

(after receiving all reports of the groups)

Morphophysiology of the Somatosensory System

Group Leader: Deolinda Lima, MD, PhD, Full Professor

Team Carvalhosa Raquel (FCT Grant)

Castro Lopes, José (MD, PhD Associate Professor)

Castro, Ana Rita (PhD Student)

Charrua, Ana (PhD Student)

Cruz, Célia (PhD Student)

Cruz, Francisco (MD, PhD Associate Professor)

Cruz, Helder (FCT Grant)

Dinis, Paulo (MD, Teaching Assistant)

Ferreira, Elisabete (Secretariat Assistant)

Galhardo, Vasco (PhD, Assistant Professor)

Gomes, Joana (Teaching Assistant)

Lopes, Cláudia (FCT Grant)

Maia, Albino Jorge (PhD Student)

Martins, Maria Isabel (Teaching Assistant)

Mendonça, Luis (Master Student)

Monteiro, Clara (FCT Grant; Teaching Assistant)

Morgado, Carla (Teaching Assistant)

Neto, Fani (PhD, Assistant Professor)

Osório, Liliana (FCT Grant)

Pereira, Carlos (FCT Grant)

Pereira, Helena (Technician)

Pinto, Marta (PhD student; teaching Assistant)

Pinto, Vitor (PhD student)

Potes, Catarina (FCT Grant)

Rebelo, Sandra Paula (PhD Student)

Reguenga, Carlos (PhD, Assistant Professor)

Safronov, Boris (PhD, Principal Investigator)

Santos, Sónia (PhD Student)

Seixas, Daniela (MD, Teaching Assistant)

Silva, António Avelino (PhD, Assistant Professor)

Tavares, Isaura Ferreira (PhD, Associate Professor)

Pais-Vieira, Miguel (Master Student)

➢ Main Achievements During 2004

A lower expression of Na channels induces a firing adaptation in spinal sensory neurons - By combining recording from spinal cord slices, intracellular labeling and computer simulation, the mechanisms of spike frequency adaptation in substantia gelatinosa neurons were studied. The calcium-dependent conductances as well as the transiently-inactivating and the delayed-rectifier potassium currents were found not to contribute to firing adaptation. In contrast, a strong adaptation could be reversibly induced in the presence of sodium channel blocker, suggesting a principal role of sodium channels. It was concluded that the cell-specific regulation of the sodium channel expression can be an important factor underlying diversity of firing patterns in spinal sensory neurons.

Intrathalamic baclofen, a GABAB receptor agonist, reduces nociceptive behaviour in the formalin test – We have extended our previous studies on the role of thalamic GABAB receptors in chronic pain to include a model of acute and tonic pain, the formalin test. Injection of baclofen, a GABAB receptor agonist, in the ventrobasal complex of the thalamus (VB) caused the reduction of the nociceptive behaviour in both acute and tonic phases of the formalin test, without causing any impairment of the muscle activity. These results point to a specific role of GABAB receptors in the processing of nociceptive input in the VB

Inflammatory pain induces changes in the expression of P2X3 and TRPV1 receptors in primary afferent neurons – The purinergic P2X3 and the vanilloid TRPV1 receptors are involved in the transduction of noxious stimuli into nerve impulses at the peripheral endings of nociceptive fibres. We have found that acute inflammation of the knee joint induces an increase in the expression of both receptors in the nociceptors that innervate the affected knee. Moreover, chronic monoarthrtitis of the ankle causes an enhancement of the P2X3 protein detected by Western blots of the dorsal root ganglia. In the urinary bladder, chronic inflammation also results in an increase in the expression of TRPV1. (P2X3 is not expressed in the urinary bladder.) The results suggest that peripheral modulation of P2X3 and TRPV1 receptors might have analgesic effects.

ERKs 1/2 are activated in the spinal cord of monoarthritic rats and its inhibition reduces the nociceptive behaviour of the animals – Extracellular signal-regulated kinases (ERKs) are involved in nociceptive processing in the spinal cord. We have observed an enhanced activation of ERKs by movement of a monoarthritic ankle, which increased as the disease progressed. Moreover, intrathecal administration of PD98059, a specific ERKs phosporilation inhibitor, caused a reduction of the allodynia and hyperalgesia observed in those animals. Therefore, inhibition of ERKs activation might be of potential use as an analgesic therapeutic option for chronic pain.

Inflammatory pain is accompanied by thalamo-cortical synchronization – The techniques for the manufacture and implantation of matrices of tungsten multielectrodes for thalamocortical extracelular recording from awake non-restricted rats were implemented. Using this technique we were able to obtain for the first time the thalamocortical neural correlate of episodes of spontaneous pain. We showed that the occurrence of paw-flinches that are the hallmark of strong inflammatory pain is accompanied by brief intervals of synchronization between thalamic and cortical somatosensory neural activity.

Chronic pain induces cognitive deficits

During 2004 we established a research line dealing with the neurobehavioral assessment of cognitive deficits induced by chronic pain. This is a highly relevant issue since chronic pain is known to cause serious psychological disturbances in human patients, but almost no research is done on animal models of chronic pain. In a series of pioneer studies we showed that monoarthritic rats have slow learning curves in two distinct behavioral tasks, when compared to naïve animals. Simultaneous measurement of the individual levels of behavioral anxiety revealed a close association between anxiety, pain and learning performance. Moreover, our preliminary results suggest that the individual naïve levels of anxiety are a good predictor of the level of post-injury hyperalgesia.

Pain control-oriented gene therapy at supraspinal levels should depress DRt functioning by the use of an antisense to noradrenergic pathway enzymes – Structural studies aimed at identifying the neurochemical nature of neurons transduced by the modified herpes simplex virus type 1 (HSV-1) from the DRt (a pain facilitatory center) and the VLM (a pain inhibitory center) revealed a massive transduction of noradrenergic neurons at four different brain areas projecting to the DRt. DRt instillation of adrenergic receptor agonists in animals suffering from chronic pain increases pain behaviour in nociceptive tests, indicating that DRt noradrenergic afferents enhance the activity of DRt pain control neurons. Following these findings, viral vectors encoding an antisense to TH, an enzyme of the metabolic pathway of noradrenalin, and carrying a promoter that will limit their expression to TH synthesizing neurons will be produced and injected in the DRt. In order to minimise local inflammatory effects and prolong the transgene expression, the construct will be based in HSV-1 amplicons.

The structural heterogeneity of the spinal cord lamina I neuronal population appears to relate to central signalling of stimulus quality – Lamina I neurons belong in four distinct structural types, all of them activated by noxious stimuli of various nature and tissue origin. Previous studies revealed that lamina I neurons projecting to different targets are activated in different amounts according to the nature of the stimulus. This was taken as suggestive that stimulus nature discrimination could involve a particular pattern of activation of supraspinally projecting lamina I neurons. Departing from the assumption that stimulus discrimination is decreased when hyperalgesia is installed due to a chronic pain inflammatory event, we investigated whether in this case the pattern of lamina I neuronal activation differs from that obtained in healthy animals. We observed that the pattern that characterizes mechanical activation of VLM-projecting neurons is altered in such a way that all neuronal groups become equally activated.

The transcription factor DRG11 is required for the differentiation of the nociceptive pathway relaying in the superficial laminae of the spinal dorsal horn but does not affect the development of the deep dorsal horn pathway – DRG11 knockout mice were previously shown to have a seriously disrupted nociceptive system, with a marked decrease of peripheral innervation by both peptidergic and non-peptidergic primary afferent neurons and almost abolished responses in acute pain behavioural tests. Primary afferent neurons were shown to develop normally but to reach the superficial dorsal horn late during embryonic development and degenerate early after birth. According to our most recent findings, this must be due to the impairment of the development of their central targets in the spinal cord: in drg11 knockout mice, noxious-evoked c-fos induction in the superficial dorsal horn is abolished, while Golgi stainings reveal a complete absence of lamina II neurons and a marked decrease of all lamina I neuronal cell types, except for multipolar neurons which are still observed in small amounts.

Topical application of vanilloids as a therapeuthic tool for visceral pain – Using transgenic mice in which the TRPV1 receptor is knocked out, we showed the fundamental role of this receptor for the occurrence of pain and hyperactivity in the urinary bladder. The distribution of nerve fibers expressing the TRPV1 receptor was studied in the human prostate. The high density of fibers found in the prostatic urethra and ejaculatory duct suggests that topical application of vanilloids in desensitising doses can be useful in the treatment of men suffering from chronic pelvic pain syndrome and prostatodynia.

Book Chapter

Published

Silva, C. and Cruz, F. - Intravesical pharmacological treatment. In: Neurogenic bladder: adults and Children. (Editores: J Corkos e E. Schick). Donitz, London. (2004)

In Press

Cruz, F., Dinis, P. and Siva, C. TRPV1 agonist therapies in bladder diseases. In: Turning Up the Heat on Pain: TRPV1 Receptors in Pain and Inflammation (Editores: Annika B. Malmberg and Keith R. Bley). Birkhauser (in press)

Lima, D. Spinothalamic Tract Neurons, morphology. Encyclopedic Reference of Pain (in press)

Original Articles

International Journals

Published

Castro, A.R., Pinto, M., Lima, D. and Tavares, I. Nociceptive spinal neurons expressing NK1 andGABAB receptors are located in lamina I. Brain Res., 1003: 77-85 (2004)

Cruz, F. Mechanisms involved in new therapies for overactive bladder Urology 63: 65-73 (2004)

Cruz, F. and Silva, C. Botulin toxin in the management of lower urinary tract disfunction. Contemporary update. Curr. Opinion Urol. 14: 329-334 (2004)

Dinis, P., Silva, J., Ribeiro, M.J., Avelino, A., Reis, M. and Cruz, F. Bladder C-fiber desensitization induces a long-lasting improvement of BPH-associated storage LUTS: a pilot study. Europ. Urol. 46:88-93; discussion 93-4 (2004)

Dinis, P., Charrua, A., Avelino, A., Yacoob, M., Bevan, S., Nagy, I. and Cruz, F. Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis. J. Neurosci. 24:11253-63. (2004)

Dinis, P., Charrua, A., Avelino, A. and Cruz, F. Intravesical resiniferatoxin decreases spinal c-fos expression and increases bladder volume to reflex micturition in rats with chronic inflamed urinary bladders. BJU Int. 94:153-7 (2004)

Ferreira-Gomes, J., Neto, F.L. and Castro-Lopes, J.M. Differential expression of GABAB(1b) receptor mRNA in the thalamus of normal and monoarthritic animals. Biochemical Pharmacology 68: 1603-1611 (2004)

Melnick, I.V., Santos, S.F.A. and Safronov, B.V. Mechanism of spike frequency adaptation in substantia gelatinosa neurons of rat. J Physiol 559: 383-395 (2004)

Melnick, I.V., Santos, S.F.A., Szokol, K., Szŭcs, P. and Safronov, B.V. Ionic basis of tonic firing in spinal substantia gelatinosa neurons of rat. J. Neurophysiol . 91: 646-655 (2004)

Santos, S.F.A., Melnick, I.V. and Safronov, B.V. Selective postsynaptic inhibition of tonic-firing neurons in substantia gelatinosa by µ-opioid agonist. Anesthesiology 101: 1177-1183 (2004)

Tavares, I. The molecular metamorphosis of embryology: implications for medical education. Med. Edu. 38: 544 (2004)

In press

Castro, A.R., Pinto, M., Lima, D. and Tavares, I. Imbalance between the expression of NK1 and GABAB receptors in nociceptive spinal neurons during secondary hyperalgesia: a c-fos study in the monoarthritic rat. Neuroscience (in press)

Cruz, C., Avelino, A., McMahon, S.B. and Cruz, F. Increased spinal cord phosphorylation of extracellular signal-regulated kinases mediates micturition overactivity in rats with chronic bladder inflammation. Eur. J. Neurosci. (in press)

Dinis, P., Charrua, A., Avelino, A., Nagy, I., Quintas, J., Ribau, U. and Cruz, F. The Distribution of Sensory Fibers Immunoreactive for theTRPV1 (Capsaicin) Receptor in the Human Prostate Europ. Urol, (in press)

Silva, J., Dinis, P., Silva, C. and Cruz, F. Terapêutica intravesical com agonistas do TRPV1. Acta Urológica (in press)

Review Articles

National Journals

Published

Cardoso-Cruz, H., Monteiro, M., Lima, D. and Galhardo, V. Efeito do antagonista do receptor de glicina (estricnina) no tempo de latência de resposta de neurónios da medula espinhal do rato: um estudo com multieléctodos. Dor, 12: 28-35 (2004)

Charrua, A., Avelino, A., Cruz, C.D. and Cruz, F. Caracterização do novo composto iodoresiniferatoxina (IRTX): efeitos no receptor vanilóide. Dor, 12: 36-40 (2004)

Cruz, C., Neto, F.L., Castro-Lopes, J.M., Cruz, F. and McMahon, S.B. A estimulação mecânica de articulações monoartríticas induz fosforilação das ERKs 1 e 2 na medula espinhal. Dor, 12: 20-27 (2004)

Galhardo, V. Mecanismos neurobiológicos da dor fantasma. Dor, 12: 12-18 (2004)

Morgado, C. and Tavares, I. Mecanismos fisiopatológicos da neuropatia diabética dolorosa. Dor, 12: 5-10 (2004)

Potes, C.S., Neto, F.L. and Castro-Lopes, J.M. Efeitos da activação de receptores GABAB do complexo ventrobasal talâmico em ratos sujeitos a testes de dor inflamatória aguda e crónica. Dor, 12: 11-19 (2004)

Silva, J., Dinis, P., Avelino, A. and Cruz, F. A dessensibilização das fibras C vesicais induz uma melhoria duradoura nos sintomas de armazenamento associados à HBP. Um estudo piloto. Acta Urológica 21: 9-16 (2004)

Communications

In International Meetings

• 1st Neuroscience Symposium; International Institute for Neuroscience of Natal, Brasil, March 2004

Avelino, A., Dinis, P., Charrua, A., Nagy, I., Quintas, J., Reis, M., and Cruz, F. Distribution of the sensory fibers imunoreactive for the TRPV1 (capsaicin) receptor in the human prostate

Castro, A.R., Pinto, M., Tavares, I. and Lima, D. Secondary hyperalgesia is associated with alterations in the expression of NK1- and GABAB-receptors in nociceptive spinal neurons

Cardoso-Cruz, H., Maia, A., Monteiro, C.M., Galhardo, V., and Lima, D. Populational changes in rat anterior cingulate cortex neuronal network induced by pain

Charrua, A., Dinis, P., Avelino, A., Nagy, I., Yacoob, M., and Cruz, F. The TRPV1 agonist anandamide is a signalling molecule in inflamed urinary bladder

Cruz, C.D., Avelino, A., McMahon, S.B. and Cruz, F. Urinary bladder inflammation increases the activation of the extracellular signal-regulated kinases 1 and 2 (ERKs 1/2)

Ferreira-Gomes, J., Neto, F.L. and Castro-Lopes, J.M. Ventrobasal complex GABAb1b receptor mRNA expression is decreased in monoarthritis

Martins I, Pinto M, Wilson, SP, Lima D. and Tavares I. Perspectives of gene therapy for pain control from supraspinal areas: a study on the dynamics of HSV-1 vector migration from the medulla oblongata.

Monteiro, C.M., Cardoso-Cruz, H., Galhardo, V. and Lima, D. Intrathecal-strychnine administration promotes a decrease in latency time response of hyperexcited spinal dorsal horn neurons

Neto, F.L., Schadrack, J., Tölle, T.R. e Castro-Lopes, J.M. Involvement of metabotropic glutamate receptors in monoarthritic pain

Pais-Vieira, M., Galhardo, V. and Lima, D. Cognitive deficits induced by persistent pain: A water maze study in the rat

Pinho, D., Morato, M., Sousa, T., Tavares, I. and Albino-Teixeira, A. The role of the caudal ventrolateral medulla in the hypoalgesia associated with hypertension

Pinto, M., Lima, D. and Tavares, I. Brainstem neurons expressing NK1 and µ-opioid receptors are not activated by the movement of a chronically inflamed joint

Rebelo, S., Osório, L., Reguenga, C., Anderson, D. and Lima, D. DRG11 is differentially required at distinct stages during development of the nociceptive system

Santos, S. and Safronov, B.V. (-Opioid agonist DAMGO selectively hyperpolarizes tonically firing neurons in rat substantia gelatinosa

• 4th Forum of European Neuroscience, FENS, Lisbon, Portugal, 10-14 July 2004

Avelino, A., Dinis, P., Charrua, A., Nagy, I., Quintas, J., Reis, M., and Cruz, F. TRPV1 (Vanilloid receptor) imunoreactive fibers in the human prostate

Castro, A.R., Pinto, M., Tavares, I. and Lima, D. Spinal neurons bearing NK1- and GABAB-receptors are involved in secondary hiperalgesia in the monoarthtritic rat

Cardoso-Cruz, H., Monteiro, C.M., Lima, D. and Galhardo, V. Effect of intrathecal administration of the glycine receptor antagonist strychnine in the latency time response of neurons in the rat spinal dorsal horn

Charrua A., Dinis P., Avelino A., Nagy I., Yacoob M., and Cruz F. Inhibition of endogenous anadamide degradation in the bladder increases reflex activity through TRPV1 activation

Cruz, C.D., Charrua, A., McMahon,S.B. and Cruz, F. Extracellular signal-regulated kinases 1 and 2 (ERKs 1/2) are involved in micturition control at the spinal cord level in cyclophosphamide (CYP)-inflamed animals

Ferreira-Gomes, J., Neto, F.L. and Castro-Lopes, J.M. Lateral thalamic nuclei GABAb1b receptor mRNA expression is regulated during monoarthritis

Martins, I., Pinto, M., Wilson, S.P., Lima, D. and Tavares, I. Dynamics of a recombinant HSV-1 vector migration from the medulla oblongata: implications for gene therapy of pain

Monteiro, C.M., Cardoso-Cruz, H., Lima, D. and Galhardo, V. Induction of bistable activity and changes in the oscillatory properties of rat spinal dorsal horn neurons following formalin injection

Neto, F., Cruz, C.D., Castro-Lopes, J.M., Cruz, F. and McMahon, S. B. Intrathecal injection of PD98059, a specific inhibitor of extracellular signal-regulated kinases 1/2 (ERKs 1/2), attenuates allodynia in monoarthritic rats

Pais-Vieira M, and Galhardo V. Cognitive deficits induced by persistent pain: a water maze study in the rat.

Pinto, M., Lima, D. and Tavares, I. Plasticity of c-fos expression at brainstem neurons in response to bending a chronically inflamed joint

Potes, C.S., Neto, F.L., and Castro-Lopes, J.M. Stereotaxic administration of baclofen, a GABAB agonist, in the thalamic ventrobasal complex attenuates allodynia in monoarthritic rats

Rebelo, S., Osório, L., Reguenga, C., Anderson, D. and Lima, D. The role of DRG11 in the development of the peripheral nociceptive system

Santos, S.F.A., Melnick, I. and Safronov, B.V. Mechanism of spike frequency adaptation in substantia gelatinosa neurons of rat

• 3rd World Congress of the World Institute of Pain, Barcelona, Spain, 21-25 September 2004

Castro, A.R., Pinto, M., Tavares, I. and Lima, D. Chronic pain is accompanied by an imbalance of excitatory and inhibitory actions upon supraspinally projecting lamina I neurons

Ferreira-Gomes, J., Neto, F.L. and Castro-Lopes, J.M. Differential expression of GABAB(1b) receptor mRNA in the thalamus of normal and monoarthritic animals

Martins, I., Pinto, M., Tavares-Marques, A., Pereira, S., Wilson, S.P., Lima, D. and Tavares, I. Gene therapy for pain control from the caudal medulla oblongata: What can we learn from studying the dynamics of HSV-1 migration

Pinto, M., Lima, D. and Tavares, I. Spinal c-fos expression in response to brief stimulation of a chronically inflamed joint

• 34th Annual Meeting of Society for Neuroscience, San Diego, California, USA, 23-27 October 2004

Castro, A.R., Pinto, M., Tavares, I. and Lima, D. Secondary hyperalgesia is accompanied by an imbalance in the expression of NK1- and GABAB-receptors in nociceptive spinal neurons

Charrua, A., Avelino, A., Cruz, C.D. and Cruz, F. Iodoresiniferatoxin (IRTX) applied topically to the rat bladder acts as potent TRPV1 agonist

Cruz, C.D., Neto, F., Castro-Lopes, J., McMahon, S.B. and Cruz, F. Extracellular signal-regulated kinases 1 and 2 (ERKs) are upregulated in the spinal cord of chronic inflamed animals and regulate visceral reflex activity and pain

Lima, D., Cardoso-Cruz, H., Monteiro, C.M. and Galhardo, V. Effect of the glycine receptor antagonist strychnine in the latency time response of rat spinal dorsal horn neurons: a multielectrode study

Martins, I., Pinto, M., Tavares-Marques, A., Pereira, S., Wilson, S.P., Lima, D. and Tavares, I. Pattern of Migration of HSV-1 from pain control areas of the caudal medulla oblongata

Potes, C.S., Neto, F.L. and Castro-Lopes, J.M. GABAB receptor activation in the thalamic ventrobasal complex reduces allodynia in monoarthritic rats

Silva, A., Charrua, A., Dinis, P., and Cruz, F. TRPV1 knockout mice do not develop bladder overactivity during acute chemical bladder inflammation

Reguenga, C., Rebelo, S., Osório, L., Anderson, D., and Lima, D. Drg11 is post-transcriptionally regulated and is required at two distinct stages during the development of the nociceptive system

Safronov, B.V., Santos, S.F.A., Melnick, I.V. and Derkach, V.A. Mechanism of spike frequency adaptation in substantia gelatinosa neurons of the rat spinal cord

In National Meetings

• 2º Congresso da Associação Portuguesa para o Estudo da Dor/Club de Anestesia Regional (APED/CAR), 13-15 October 2004

Ferreira-Gomes, J., Neto, F. and Castro-Lopes, .JM. Expressão do ARNm para a subunidade 1b do receptor GABAB (GABAB(1b)) no tálamo de ratos normais e monoartríticos

Martins, I., Pinto, M., Wilson, S.P., Lima, D. and Tavares, I. Terapia genética aplicada a áreas do sistema endógeno de controlo da dor. Estudos da dinâmica de migração do HSV-1 e de caracterização neuroquímica de neurónios transfectados

• XXXIX Reunião da SPME-BC, 4-6 November 2004

Cruz, C.D., Neto, F., Castro-Lopes, J.M., McMahon, S. B. and Cruz, F. Phosphorylation of Extracellular signal-regulated kinases (ERKs) in the spinal cord is upregulated by chronic inflammation

Ferreira, D., Cruz, C.D., McMahon, S. B. and Cruz, F. Identification of the primary afferent fibers responsible for the activation of extracellular signal regulated kinases (ERKs) in the spinal cord by intravesical instillation of vanilloids

• X Congresso Luso-Brasileiro de Anatomia, November 2004

Martins, I., Pinto, M., Wilson, S.P., Lima, D. and Tavares, I. Transporte retrógrado do vírus HSV-1 e libertação anterógrada dos seu produto de expressão a partir de áreas do bolbo raquidiano envolvidas no controlo da dor

Reports

Lectures

In International Meetings

Castro-Lopes, J.M. Modulation of nociceptive transmission by the spinal GABAergic system. 7th Congress of the Turkish Pain Society, Istambul, May 2004

Lima, D. Differential expression of NK1 and GABAB receptors in spinal neurons. Spring Pain Research Conference, May 2004

Galhardo, V. Pain-induced immediate re-organization in spinal populations of somatosensory neurons. Simposium. 4th Forum of European Neuroscience, FENS, Lisbon, July 2004

Tavares, I. Central administration of viral vectors for pain control. 4th Forum of European Neuroscience, FENS, Lisbon, July 2004

Lima, D. and Tavares, I. Pain facilitation from the brain; a new target for descending pain control manipulation. 3rd World Congress of World Institute of Pain, Barcelona, September 2004

Cruz, F. Intravesical vanilloids for the treatment of overactive bladder. Department of Pharmacology. McGill University. Montreal, Canada, October 2004

Cruz, F. Chronic bladder inflammation: Targeting bladder sensory pathways to alleviate pain and hyperreflexia. Pain Rounds. McGill University. Montreal, Canada, October 2004

In National Meetings

Castro-Lopes, J.M. Trapézio sem rede – Barreiras na prescrição de opióides – realidade ou ficção? 2º Convénio da ASTOR e 11as Jornadas da Unidade de Dor do Hospital Garcia de Orta, Almada, January 2004

Castro-Lopes, J.M. Plano Nacional de Luta Contra a Dor. 4º Curso de Enfermagem Sobre Dor, Porto, January 2004

Rebelo, S. “Técnicas Básicas de Biologia Molecular” a convite do Serviço de Microbiologia da FMUP, Porto, March 2004

Castro-Lopes, J.M. Simpósio “Dor, Problemática e perspectiva terapêutica actual”, Importância da dor como 5º sinal vital. Lisbon, April 2004

Galhardo, V. Da dor aguda à dor crónica: mecanismos fisiológicos. 2º Congresso APED/CAR, Lisbon, October 2004

Cruz, C.D. Neuronal signalling by ERKs: key elements in pain. IBMC Advanced Course on Oxidative Stress and Cell Signalling, October 2004

Rebelo, S. The mechanism of fertilization. The morphology of pronucleus and the initial steps of embryo development, 2º Congresso Português de Medicina da Reprodução, Espinho, October 2004

Castro-Lopes, J.M. Fisiopatologia da dor neuropática. II Curso Internacional de Técnicas Anestésicas Loco Regionais em Ortopedia, Coimbra, November 2004

Castro-Lopes, J.M. Dor na doença oncológica – Uma intervenção multi e pluridisciplinar. 5º Congresso Nacional de Enfermagem Oncológica, Viana do Castelo, November 2004

Patents and Prizes

Costa, J.A., Costa, J.L., Castro, A.R., Tavares, I. and Lima, D. Projecto de Investigação científica na pré-graduação da Universidade do Porto e Fundação Ilídio Pinho, Porto, 2004

Cruz, F. and Silva, C. Primeiro prémio da British Medical Association Medical Book Competition, com o livro Neurogenic bladder: adults and children. (Editores: J Corkos e E. Schick). Donitz, London, 2004

Cruz, C.D., Avelino, A., McMahon S.B. and Cruz, F. 1º Prémio Grunenthal, Dor 2004. “As cínases de regulação extracelular –1 e –2 (ERK 1 e 2) medeiam a dor e a actividade reflexogénica da bexiga causadas pela inflamação crónica”. 1º Prémio Grunenthal, Dor 2004

Ferreira-Gomes, J., Neto, F. and Castro-Lopes, .JM. Menção Honrosa Extra-Concurso com a Comunicação Oral “Expressão do ARNm para a subunidade 1b do receptor GABAB (GABAB(1b)) no tálamo de ratos normais e monoartríticos” no 2º Congresso APED/CAR, Lisboa, October 2004

Galhardo, V., Cardoso-Cruz, H., and Monteiro, C. “Representação cortico-talâmica da dor espontânea”, 2º lugar do Prémio Grunenthal, Dor 2004

Martins, I., Pinto, M., Lima, D. and Tavares, I. Prémio Internacional de Investigação CESPU 2004 – 2ª Menção Honrosa com o trabalho: “Perspectivas da aplicação da terapia génica no controlo da dor por manipulação de áreas supraspinhais”

Martins, I., Pinto, M., Steven P Wilson, Lima, D. and Tavares, I. Menção Honrosa Extra-Concurso com a Comunicação Oral “Terapia genética aplicada a áreas do sistema endógeno de controlo da dor. Estudos da dinâmica de migração do HSV-1 e de caracterização neuroquímica de neurónios transfectados ” no 2º Congresso APED/CAR, Lisbon, October 2004

Pais-Vieira, M. and Galhardo V. Défices cognitivos induzidos por dor crónica: um estudo por water maze no rato. Menção Honrosa no âmbito do Prémio Grunenthal, Dor 2004

Projects Concluded (Only those which were concluded in 2004)

“Role of sensory neurons expressing the vanilloid receptor in urinary and articular pathology. An experimental and clinical study”; 2001–2004; Fundação para a Ciência e a Tecnologia, Project no. POCTI/NSE/32466/1999 (F Cruz)

“Cell-specific firing patterns in spinal sensory neurones”; 2001-2004; Fundação para a Ciência e  Tecnologia, Project no. 32371/99 (B. Safronov em colaboração com Deolinda Lima)

“Discriminação sensorial na dor crónica: papel da modulação de neurónios espinhais pelos respectivos alvos”. Ano 2004. Projecto de Investigação científica na pré-graduação da Universidade do Porto e Fundação Ilídio Pinho (I Tavares)

Dissertations

PhD Theses concluded

MSc Theses concluded

Student: Miguel Pais Vieira

Supervisor: Vasco Galhardo

Title: PLACEBO: Contributos da neurobiologia e filosofia nas ciências cognitivas actuais

University: Faculdade de Filosofia da Universidade Católica

Organization of Seminars

Seminars

“Selective postsynaptic inhibition of tonic-firing neurons in substantia gelatinosa by u-Opioid agonists”, Sónia Santos

“Nociceptive spinal neurons expressing KN1 and GABAB receptors are located in lamina I”, Ana Rita Castro

“Approaches to restore function following SCI: overview of the Miami Project”, Mary Eaton

“Intravesical resiniferatoxin decreases spinal c-fos expression and increases bladder volume to reflex micturition in rats with chronic inflamed urinary bladders”, Paulo Dinis

“Bladder C-fiber desensitization induces a long-lasting improvement of BPH-associated storage LUTS: apilot study”, Paulo Dinis

“Differential expression of GABBAB(1b) receptor mRNA in the thalamus of normal and monoarthritic animals”, Joana Gomes

“Inhibition of FGF in development and disease”, Robert Friesel

Scientific Meetings

“International Meeting on Neuropathic Pain - Changing Paradigms in Diagnosis and Treatment”, Madrid, JM Castro Lopes (member of The Scentific Committee)

4th Forum of European Neuroscience, Lisbon, July 2004 – JM Castro Lopes (Local Committee Chairman)

Technical Workshop at the FENS Forum 2004: Gene therapy for pain control, Lisbon, July 2004 – I Tavares

Advanced Course in Computational Neurosciences, Óbidos, August-September 2004 – V Galhardo (Local Organizer)

Workshop “Introduction to rodent behaviour testing – Theory and Applications”, IBMC, Porto, M Pais-Vieira

Advanced Courses

Graduate Course in Pain Medicine – JM Castro-Lopes (Organizer)

Graduate Program in Basic and Applied Biology (GABBA) – JM Castro-Lopes (Coordenation)

Plans and Needs for 2005

Objectives for 2005

Electrical properties of spinal nociceptive neurons

• To characterize tonic firing neurons, adapting firing neurons and delayed-onset firing neurons in substantia gelatinosa as excitatory or inhibitory interneurons.

• To determine transmitters they release and the type of postsynaptic receptors they act on.

• To study whether transmitters released by these three types of neurons depend on location of post-synaptic neuron in lamina I, II (SG) and III.

Receptor plasticity in chronic pain

• To complete the detailed mapping of the changes induced by chronic pain in the expression of metabotropic receptors in the thalamus, namely by finishing the studies related with the expression of the different subunits of GABAB receptors and of the opioid receptors.

• To expand the studies on the involvement of P2X3 and TRPV1 receptors in nociception by studying the effects of the pharmacological modulation of those receptors.

Osteoarthritic pain

• To start a new study on the innervation of subchondral bone in the knee joint and its changes in animal models of ostheoarthritis and in humans.

• To start a new study on the fMRI activation pattern elicited by stimulation of human ostheoarthritic knees and its change by acupuncture

Involvement of the ERKs cascade in nociception

• To evaluate the involvement of ERK in bladder hyperreflexia by assessing the total amount of ERK (active and non-active) and identify the spinal cells expressing the active form of ERK.

• To evaluate the effects of manipulating the ERK cascade in an animal model of spinal cord injury (SCI)

Epidemiology of pain

• To start a new study on the epidemiology of chronic pain in Portugal and its socio-economic impact

Neurophysiological recording from awake behaving animals

• To expand the scope of our multielectrode recordings in awake animals to study the role of thalamocortical spontaneous oscillations in the genesis and maintenance of chronic pain

• To ellucidate key features of thalamocortical sensory perception, such as the emergence of post-injury low-frequency thalamic oscillations, and the way these oscillations modulate the processing of somatosensory information.

• To explore the use of nerve-implantable multielectrodes as a device to create a perceptional bionic interface for tactile stimuli. This will be used to study the effects of long-term electrical peripheral stimulation upon cortical organization of sensorial maps, and to later devise a bionic approach to restore the natural topography of cortical deafferented areas.

Pain-induced cognitive impairment

• To expand the preliminary results so far obtained and to uncover other specific cognitive impairments caused by chronic pain. In particular we will focus on how chronic pain affects behavioral performance in attention-related tasks, and whether it does affect working-memory and reference-memory.

• To look at how chronic pain does affect reward and avoidance foraging strategies, or reinforcement learning tasks, and how does the behavioral performance of chronic pain animals compare with CNS lesioned animals.

Gene therapy for pain control

• To evaluate the analgesic outcome of manipulation of opioid transmission at the DRt through pain behaviour analysis after local administration of HSV-1 containing either a sense or an antisense to pre-pro-enkephalin gene

• To produce a HSV-1 amplicon construct with a TH promoter and a TH sense or antisense transgene

• To evaluate the effects of DRt injection of both constructs in nociceptive tests

• To evaluate, by the use of pharmacological approaches, whether down-expression of GABAB receptors in the DRt and VLM during chronic pain affect GABA-mediated pain control effects elicited in each nucleus; In the case GABAB receptor-mediated transmission is disrupted, use lentivirus constructs to normalise GABAB receptor expression

Lamina I neurons in pain discrimination

• To study the pattern of activation of VLM-projecting lamia I neurons by acute cutaneous thermal pain in normal and hyperalgesic animals

• To evaluate whether lesionning the VLM before noxious stimulation alters the activation pattern in both situations

Embryonic development of the nociceptive system

• To look for apoptosis in the spinal cord in early stages of embryonic development, and use biological markers of different types of dorsal horn neuronal precursor cells in order to characterize which are the neurons requiring DRG11 to fully differentiate

• To produce a conditional knockout to elucidate the functional meaning of the early (E12.5) and late (E17.5) DRG expression

• To evaluate whether the two splicing isoforms of DRG11 are differentially expressed at the two embryonic stages

• To uncover genes that are downstream to drg11 in the drg11 pathway

Analgesia produced by topical application of vaniloid substances

• To investigate whether VR1 receptor endogenous agonists other than anandamide are increased in inflamed bladders and elucidate their effects.

• To study the action of vanilloid molecules in the hyperreflexia accompanying benign prostatic hyperplasia produced in an animal model.

On Going Financed Projects

1. "Involvement of the transcription factor DRG11 in the development of the sensory system; neuronal differentiation and connectivity”; 2001–2005; Fundação para a Ciência e Tecnologia, Projecto nº POCTI/NSE/32357/1999 (D Lima)

2. “Representation of Stimuli As Neural Activity”; 2002–2005; European Union, ROSANA Projecto n.º IST-2001-34892 (D Lima)

3. “Pain control from the brain: gene therapy in the treatment of chronic pain”; 2005-2008; Projecto da Fundação Bial nº 15/04 (D Lima)

4. “Nociceptive spinal neuronal differentiation during embruonic development as a primary target of the transcription factor DRG11”; 2005-2008; Fundação para a Ciência e Tecnologia, Projecto n.ºPOCTI/NEU/59093/2004 (D Lima)

5. “The brain in pain: cognitive impairment in animal models of chronic pain”; 2005-2008; Fundação para a Ciência e Tecnologia, Projecto n.º POCTI/SAU-NEU/63034/2004 (D Lima

6. “Role of metabotropic receptors in the thalamic processing of chronic pain”; 2001–2006; Fundação para a Ciência e Tecnologia, Projecto n.º POCTI/NSE/32375/1999 (JM Castro-Lopes)

7. “Neorobiological mechanisms of pain in osteoarthritis”; 2005-2008; Fundação para a Ciência e Tecnologia, Projecto n.º POCTI/SAL-NEU/60853/2004 (JM Castro-Lopes)

8. “Toward an integrated network for pain management programmes in Europe”. Specific Support Action ERA-NET nº 515760, European Commission 6th Framework Programme (JM Castro-Lopes – Portuguese coordinator)

9. “Sensory mechanisms of overactive bladder”; 2005-2008; Fundação para a Ciência e Tecnologia, Projecto n.º POCTI/SAU-NEU/55983/2004 (F Cruz)

10. "Gene therapy for the control of chronic pain: role of the supraspinal pain modulatory system”; 2002–2005; Fundação para a Ciência e Tecnologia, Projecto nº POCTI/NSE/38952/2001 (I Tavares)

11. "Hipoalgesia associada à hipertensão: mecanismos e importância da activação do sistema renina-angiotensina na hipertensão causada pelo bloqueio de receptores da adenosina”; 2003-2006; Fundação para a Ciência e Tecnologia, Projecto n.º POCTI/NSE/45409/2002 (I Tavares – em colaboração com A Albino-Teixeira, Instituto de Farmacologia e Terapêutica )

12. “Excitability of spinal and peripheral sensory neurons and its modulation by local anesthetics”; 2002-2006; Fundação para a Ciência e Tecnologia, Projecto nº 41050/BCI/2001 (B Safronov)

13. “Mechanisms of spinal sensory processing: a study of synaptic connectivity and modulation of intrinsic firing in Substantia Gelatinosa neurons”; 2005-2008; Fundação para a Ciência e Tecnologia, Projecto nº POCTI/SAU/NEU/56388/2004 (B Safronov)

14. “Functional dynamics of pain: sensorial reorganization of neuronal populations induced by chronic pain and microstimulation”; 2002–2005; Fundação para a Ciência e Tecnologia, Projecto n.º POCTI/NSE/38995/2001 (V Galhardo)

15. “Central pain syndromes; the role of thalamocortical spontaneous oscillations in somatosensory enhancement”; 2005-2008; Fundação para a Ciência e Tecnologia Projecto n.º POCTI/SAU-NEU/55811/2004(V Galhardo)

16. “Re-establishment of somatosensory awareness using high density direct nerve fiber microstimulation”; 2005-2007; Fundação para a Ciência e Tecnologia Projecto n.º POCTI/SAU-NEU/59383/2004 (V Galhardo)

17. “A consciência da dor: alterações induzidas por dor crónica nos mecanismos neurobiológicos de aprendizagem, atenção e recompensa”; Projecto da Fundação Bial (V Galhardo)

Inter-institutional Cooperation

International

University South Carolina, USA, Prof. Steven P. Wilson

California Institute for Technology (CalTec), USA, Prof. David Anderson

King’s College of London, UK, Prof. Stephen McMahon

Imperial College, London, UK, Prof. Istvan Nagy

National

Instituto de Farmacologia e Terapêutica (FMUP), Prof. António Albino-Teixeira

Grupo de ?????????? (IBMC), Drª Clara Sã Miranda

Other Relevant Information

This is a rather large group that works together in the investigation of several aspects of the mechanisms underlying the processing of physiological and pathological pain. Although sharing funding, equipment and knowhow, the group is made up by several subgroups which are organized around particular areas of research and are supervised by one or two PIs.

The large amount of work being carried out by a group of such dimension prompts the urgent acquisition of technical support through the hiring of two technicians to work with the entire group, one at IBMC and the other at FMUP. It should be noted that the technician Helena Pereira is no longer in the team.

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