UC San Diego

Toll-Like Receptor 3 (TLR3) is a receptor of the innate immune system. TLR3 exists within spinal glial cells which are known to play an important role in facilitating spinal pain processing. We hypothesized that activation of these spinal TLR3 would cause glial activation and initiate an enhanced response to noxious stimuli. Using rats with chronic lumbar intrathecal (IT) catheters these studies demonstrated the following observations. 1) IT Polyinosine -polycytidylic acid (Poly I:C, 100[mu]g) resulted in a fall in the tactile threshold (tactile allodynia : TA) with no change in thermal escape by 24 hrs. The TA lasted at least though 4 days. 2) Rats receiving IT minocycline, pentoxifylline, ketorolac and valdecoxib prior to IT Poly I:C showed significant decreases in the persistent pain state. 3) Rats receiving IT Poly I:C and sacrificed at day 1 showed increases in astrocyte and microglia activation in the superficial lamina and deep lamina of the dorsal horn as well as in the ventral horn. 4) Activation of astrocytes and microglia diminished at day 4. 5) Rats receiving intrathecal pretreatments of glial inhibiting drugs (minocycline and pentoxifylline) as well as COX blocking drugs (ketorolac and valdecoxib) prior to intrathecal Poly I:C and sacrificed at day 1 showed normal levels astrocyte and microglia activation, indicating an inhibition of the nociceptive cascade. 6) IT Poly I:C produced no change in nocturnal behavior. These results indicate that activation of TLR3 can initiate a persistent cascade of facilitated pain processing, mediated at least in part by a glially related cascade