Dor neuropática: contribuição da inflamação para a sua gênese e proposta de intervenção terapêutica

Abstract

Neuropathic pain has been currently widely studied. However, the pathophysiological processes that lead to its genesis are poorly known and, consequently, there is a paucity of therapeutic tools to treat the patients with these chronic painful conditions. Initially, the time course for development of hyperalgesia and allodynia after chronic constriction injury (CCI) of rat sciatic nerve was examined. Hyperalgesia was detectable three days after CCI and allodynia was detectable seven days afterwards. Next, we observed the intraneural, but not perineural, administration of dexamethasone at the moment of CCI (day 0) delayed the development of both hyperalgesia and allodynia. Then, we evaluated for 33 days the effect induced by a perineural implant containing dexamethasone on the development of mechanical allodynia. This systemic treatment prevented the development of allodynia for weeks, whereas the allodynia remained unaffected when the implantation was performed 12 days after CCI, a time point at which allodynia was fully developed. The delay of allodynia development is associated with peripheral antineuroinflammatory effect, as we observed reduced activation of nuclear factor B in dorsal root ganglia in rats subjected to dexamethasone perineural implantation simultaneously to constriction. As well as dexamethasone, minocycline induces pleiotropic anti-inflammatory effects, but in contrast to dexamethasone, minocycline inhibits fully established allodynia in models of neuropathic pain. However, minocyclines antibiotic and divalent cation (Ca2+; Mg2+) chelating effects detract from its potential clinical utility. Therefore, it was investigated the potential effect induced by a non-antibacterial, non-chelating minocycline derivative on the allodynia induced by CCI in mice. Either minocycline or its derivative (12S-hydroxy-1, 12-pyrazolinominocycline PMIN i.p. injection) induced antiallodynic effect when administered 21 days after CCI. An initial investigation of its anti-inflammatory mechanisms was performed and showed that this chemically modified tetracycline reduced the PGE2 production by cultured primary rat microglial cells stimulated with lipopolysaccharide (LPS) and inhibited toll-like receptor 2 (TLR2) and TLR4 signaling in transfected HEK293 cells stimulated with PAM3CSK4and LPS, respectively. The present study reinforces the evidence that inflammatory/immune response is essential for the development of experimental neuropathic pain andsupports the conduction of clinical studies to evaluate the usefulness of PMIN as analgesic, especially because chemically modified tetracyclines are potentially safer than conventional tetracyclines as they do not exhibit antibacterial and chelating activities.