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Hypersensitivity after tissue injury is an expression of neuronal plasticity in the central nervous system. This has been explored most extensively using in vitro preparations and animal models of inflammatory pain and chemical irritation. For pain after surgery, a similar process has been proposed. In the present study, we examined dorsal horn neuron (DHN) sensitization using the plantar incision model for post-operative pain. In behavioral experiments, the effect of a local anesthetic injection (or saline vehicle) 15min before plantar incision on pain behaviors several days after incision was studied. Bupivacaine injection before incision prevented pain behaviors until 4h afterwards; injection after incision produced the same effect. One day after incision, pain behaviors were not different between rats injected with saline or bupivacaine. In neurophysiologic experiments, however, bupivacaine injection blocked activation of DHNs during incision. One hour after incision, expansion of receptive fields (RFs) to pinch and increased background activity occurred in 14 of 16 neurons in the saline group but only in two of 22 neurons in the bupivacaine group. The difference was not due to a systemic effect of bupivacaine. Ten sensitized neurons were studied using the injection of bupivacaine 90min after incision. Increased background activity (n=7) and expanded RFs (n=7) were reversed by bupivacaine. Sensitization was re-established in seven of eight neurons 2h after injection as the local anesthetic dissipated. These results indicate that activation of DHNs during plantar incision and sensitization 1h later are not necessary for subsequent pain behaviors. Because sensitization was reversed 90min after plantar incision and then re-established as the local anesthetic effect diminished, enhanced responsiveness of DHN requires ongoing afferent input during the first day after incision.

Fundação de Amparo a Pesquisa no Estado do Rio Grande do Sul / Gout attack is characterized severe joint pain and inflammation with concomitant accumulation of monosodium urate (MSU) crystals. However, gout and the mechanisms responsible for the acute attacks are poorly understood, leading to improper treatment of the patient and reducing the quality of life. Polyamines (putrescine, spermidine and spermine) are involved in inflammatory nociceptive processes and have not been investigated to date. Therefore, the aim of the present study was to investigate the involvement of polyamines in the development of acute gout attack. Arthritis score, a compound measure of joint compromise that considers edema formation, erythema and paw position, mechanical hyperalgesia and inflammatory parameters were measured in an acute gout attack model in male mice induced by intra-articular (i.a.) injection of MSU, H2O2, phorbol 12-myristate 13-acetate (PMA), L-ornithine or polyamines (putrescine, spermidine, spermine). All these algogenic agents increased arthritis score in a dose-dependent manner with ED50 of 0.73 (0.4-1.1) mg/site for MSU, 2.3 (1.5-3.5) μmol/site for H2O2, 3.5 (2.1-5.6) nmol/site for PMA, 0.6 (0.3-1.1) μmol/site for L-ornithine, 0.8 (0.4-1.7) μmol/site for putrescine, 3.6 (2.6-5.1) μmol/site for spermidine and 0.1 (0.06-0.2) μmol/site for spermine. All tested algogenic agents caused joint edema and nociception, except putrescine, which increased only arthritis score. α-Difluoromethylornithine (DFMO; ornithine decarboxylase ODC - inhibitor, i.a.) prevented MSU-, H2O2-, PMA-, L-ornithine-induced nociception, but not edema. On the other hand, DFMO did not prevent spermine-induced edema and nociception. DFMO prevented MSU-induced increase of ODC activity. Our results indicate that polyamines contribute to acute gout attacks, suggesting that inhibitors of polyamine synthesis may be potential therapeutic agents for the treatment and prophylaxis of gout. / O ataque agudo de gota é caracterizado por dor intensa e inflamação combinados com o acúmulo de cristais de urato monossódico (MSU). No entanto, a gota e os mecanismos responsáveis pelos ataques agudos ainda estão mal compreendidos, levando ao tratamento inadequado dos pacientes e reduzindo a qualidade de vida. As poliaminas (putrescina, espermidina e espermina) estão envolvidas em processos nociceptivos inflamatórios, e não foram investigadas até o momento, por conseguinte, o objetivo do presente estudo foi investigar o envolvimento das poliaminas no desenvolvimento do ataque de gota aguda em camundongos. Para isso, o escore de artrite (conjunto de somatórios de medidas que considera a formação de edema, eritema e posição da pata tratada do animal), hiperalgesia mecânica e parâmetros inflamatórios foram medidos em um modelo de ataque agudo de gota em camundongos machos, induzidos por uma injeção intra-articular de (i.a.) MSU, H2O2, forbol 12-miristato 13-acetato (PMA), L-ornitina ou poliaminas (putrescina, espermidina, espermina). Todos os agentes algogênicos aumentaram o escore de artrite de um modo dose dependente com um DE50 de 0,73 (0,4-1,1) mg/sitio de MSU, 2,3 (1,5-3,5) μmol/sitio de H2O2, 3,5 (2,1-5,6) nmol/sitio para PMA, 0,6 (0,3-1,1) μmol/sitio para a L-ornitina, 0,8 (0,4-1,7) μmol/sitio para a putrescina, 3,6 (2,6-5,1) μmol/sitio para a espermidina e 0,1 (0,06-0,2) μmol/sitio para espermina. Todos os agentes algogênicos testados causaram edema articular e nocicepção, exceto a putrescina, que aumentou apenas o escore de artrite. α-Difluorometilornitina (DFMO; inibidor da ornitina descarboxilase - ODC) preveniu a nocicepção induzida por: MSU, H2O2, PMA, L-ornitina, mas não o edema. Por outro lado, DFMO não preveniu a nocicepção e o edema induzido por espermina. DFMO preveniu o aumento da atividade da ODC induzido por MSU. Os nossos resultados indicam que as poliaminas estão envolvidas no ataque agudo de gota, sugerindo que os inibidores da síntese de poliaminas podem ser potenciais agentes terapêuticos para o tratamento e profilaxia da gota.