The Study Of The Signal Convergent Mechanisms Underlying Rat Pain-related Behaviors Induced By BmK I, A Sodium Channel Site3Specific Modulator

As a novel pain model, many clinical pain symptoms could be well mimicked bysubcutaneous injection of BmK I, a sodium channel site3specific modulator, in therat hand paw. However, the knowledge about the peripheral and spinal signalingnetworks underlying rat pain-related behaviors induced by BmK I remain unclear. Inthis study, animal behavioral testing methods, pharmacological, immunological andelectrophysiological techniques were employed to approach the following results:1. mTOR signaling pathway is involved in the transmission of peripheralnociceptive information induced by BmK IIntraplantar injection (i.p.) of BmK I (10μg) induced the activation of mTOR, p70ribosomal S6protein kinase (p70S6K) and eukaryotic initiation factor4E-bindingprotein1(4E-BP1) in both sides of rat L5-L6DRG neurons. The activation peakedat2h and recovered at1day after i.p. injection of BmK I. Compared with the na vecontrol group, the ratio of p-mtor/p-p70S6K/p-4EBP1immune-reactive (IR)neurons in different neuron types were significantly increased. Meanwhile, the celltypological component of p-mtor/p-p70S6K/p-4EBP1IR neurons were alsochanged in variant manner. These results suggested that mTOR signaling pathwayplayed crucial roles in the transmission of peripheral nociceptive information.2. Spinal mTOR signaling cascades mediate rat pain related behaviors inducedby BmK IIntraplantar injection of BmK I (10μg) induced the activation of mTOR, p70S6Kand4E-BP1in rat L5-L6spinal neurons. mTOR, p70S6K and4E-BP1wereactivated not only in the ipsilateral spinal cord but also in the contralateral side,peaked at1-2h and recovered at1day after i.p. injection of BmK I. In addition,intrathecal (i.t.) injection of rapamycin or CCI-779, the specific inhibitor of mTOR,reduced spontaneous pain responses, attenuated unilateral thermal and bilateral mechanical hypersensitivity elicited by BmK I. Interestingly, post-treatment withrapamycin could relieve the pain sensation as well. These results revealed thatmTOR signaling pathway is mobilized in the induction and maintenance ofpain-triggered hypersensitivity.3. p38-dependent activation of spinal microglia may contribute to the centralsensitization induced by BmK IIn the current study, microglial activation could be elicited in both sides of L4-L5spinal cord by i.p. injection of BmK I. The phosphorylated p38/MAPK in L4-L5spinal cord was almost co-located with OX-42, a specific marker of microglia. BmKI-induced rat unilateral thermal and bilateral mechanical pain hypersensitivity couldbe dose-dependent attenuated at4-8h by i.t. injection of SB203580, a specificinhibitor of p-p38. It suggested that BmK I-induced microglial activation might bemediated by the phosphorylation of p38. Combining with previous studies, thepresent results revealed that p38-dependent microglial activation contributes topain-related central sensitization induced by BmK I.4. Dynamic responses of thalamocortical network in BmK I-induced painBmK I-induced neuronal activities were simultaneously recorded from primarysomatosensory cortex (SI), anterior cingulate cortex (ACC), medial dorsal (MD) andventral posterior (VP) thalamus by using a multi-channel, single-unit recordingtechnique. Following findings emerged from this study:1) According to the answeringmode, all319recorded neurons could be devided into excitable, inhibitable andresting type.2) BmK I induced changes in the amount of information flow amongdifferent brain areas, including increases in the information flow from the cortex tothe thalamus and from the medial to lateral pathway. In conclusion, BmK I animalpain model is a well-established easy-to-use model for its simple thalamocorticalanswering mode.