RESUMO
Neuropathic pain (characterized by hyperalgesia and allodynia to mechanical and thermal stimuli) causes cellular changes in spinal dorsal horn neurons, some of which parallel those in synaptic plasticity associated with learning. Ubiquitin C-terminal hydrolase (UCH) appears to play a key role in long-term facilitation in Aplysia. The cooperation of UCH with the proteolytic enzyme complex known as the proteasome is required for the degradation of a number of signaling molecules within the cell that may remove normal restraints on synaptic plasticity. We have used electrophysiology, in situ hybridization histochemistry, semiquantitative RT-PCR, Western blotting, and in vivo behavioral reflex analysis to investigate the ubiquitin-proteasome system in a model of neuropathic pain. In neuropathic animals, ionophoretic application of selective proteasome inhibitors attenuated dorsal horn neuron firing evoked by normally innocuous brush or cold stimuli and by noxious mustard oil stimuli. In control animals, only mustard oil-evoked responses were inhibited. Intrathecal administration of proteasome inhibitors attenuated hyperalgesia and allodynia in neuropathic rats. Expression of UCH-L1 (a rat homolog of Aplysia neuronal UCH and of the human UCH-L1, also known as PGP 9.5) and its mRNA were selectively increased within the ipsilateral dorsal horn of neuropathic rats, supporting the idea of a role for the ubiquitin-proteasome system in nociceptive processing. Proteasome inhibitors selectively attenuate allodynic and hyperalgesic responses in neuropathic pain, with some reduction in normal nociceptive, but not non-nociceptive responses, and potentially represent a novel therapeutic strategy for neuropathic pain.
Assuntos
Cisteína Endopeptidases/metabolismo , Complexos Multienzimáticos/metabolismo , Dor/fisiopatologia , Neuropatia Ciática/fisiopatologia , Ubiquitina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Animal , Modelos Animais de Doenças , Eletrofisiologia , Inibidores Enzimáticos/administração & dosagem , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Hibridização In Situ , Injeções Espinhais , Iontoforese , Ligadura , Masculino , Complexos Multienzimáticos/antagonistas & inibidores , Dor/tratamento farmacológico , Dor/etiologia , Medição da Dor , Células do Corno Posterior/efeitos dos fármacos , Células do Corno Posterior/fisiopatologia , Complexo de Endopeptidases do Proteassoma , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reflexo/efeitos dos fármacos , Neuropatia Ciática/complicações , Neuropatia Ciática/tratamento farmacológico , Tioléster Hidrolases/genética , Tioléster Hidrolases/metabolismo , Ubiquitina TiolesteraseRESUMO
Neuropathic pain, arising from nerve injury, results in a chronic and debilitating form of pain that in the past has been poorly diagnosed and treated. During the past few years, intensive research has resulted in major progress towards understanding the basic mechanisms that contribute to this condition, and the renewed possibility of safe and effective medicines. Indeed, the next few years should see the first fruits of this labour reaching the market place and, with them, the opportunity to assess whether the scientific advances achieved have resulted in significant clinical improvement. In this article, some of the key compounds that will lead this charge and the clinical results obtained so far are discussed.