The Roles Of Spinal Protein Kinases In Bee Venom-induced Pathological Pain

Pathological pain is a common clinical symptom characterized by a persistent spontaneous pain and hyperalgesia. To unravel the mechanisms of pathological pain, the bee venom model was used to evaluate the roles of spinal protein kinases in development of pathological pain. The bee venom (BV) model is a novel pathological pain model characterized by containing not only a persistent spontaneous pain process but also a long-term hyperalgesia (including primary thermal and mechanical hyperalgesia and secondary thermal hyperalgesia). This model mimics clinical pathological pain well and was found to be superior to the traditional pain models such as the formalin test and capsaicin model, etc. Previous studies have proved that spinal protein kinases (PKs) mediate the transmission of nociceptive information. But it still remains unclear that whether they play the same role in the pain and hyperalgesia with different characteristics. In this study, behavioral observation was adopted to evaluate the roles of spinal PKC and cAMP-PKA intracellular signal pathways in BV-inducedpathological pain, and the results are as follows:1. The roles of spinal PKC and cAMP-PKA intracellular signal pathways in induction and maintenance of the BV-induced persistent spontaneous painInhibitors of PKC > adenylyl cyclase (AC) and PKA: chelerythrine chloride(CH)^ SQ22536 and H-89 were used in the present study, hi BV pain model, intrathecal (i.t.) pre-treatment with CH (0.01, 0.1 and 1 nmol), SQ22536 (0.1, 0.5 and 1 nmol) and H-89 (0.001, 0.01 and 0.1 nmol) resulted in a dose-dependent suppressive effect on the flinching reflex compared with the control (pre-saline or pre-DMSO) group. I.t. post-treatment with SQ22536 (1 nmol) had no suppressive effect when compared with the control (post-saline) group. However, i.t. post-treatment with CH (1 nmol) and H-89 (0.1 nmol) could produce significant inhibition of the flinching reflex when compared with the control (post-saline or post-DMSO) group.2. The roles of spinal PKC and cAMP-PKA intracellular signal pathways in induction and maintenance of the BV-induced contralateral thermal hyperalgesiaI.t. pre-treatment with CH (0.01, 0.1 and 1 nmol), SQ22536 (0.1, 0.5 and 1 nmol) and H-89 (0.001, 0.01 and 0.1 nmol) resulted hi a dose-dependent suppressive effect on contralateral thermal hyperalgesia compared with the control (pre-saline or pre-DMSO) group. I.t. post-treatment with CH (1 nmol), H-89 (0.1 nmol) and SQ22536 (1 nmol) could produce significant inhibition of the contralateral thermal hyperalgesia when compared with the control (post-saline or post-DMSO) group.3. The roles of spinal PKC and cAMP-PKA intracellular signal pathways in induction and maintenance of the BV-induced primary thermal hyperalgesiaI.t. pre-treatment with SQ22536 (0.1, 0.5 and 1 nmol) or H-89 (0.001, 0.01 and 0.1nmol) had no apparent suppressive effect on primary thermal hyperalgesia, same effect observed in primary thermal hyperalgesia with i.t. post-treatment with SQ22536 (1 nmol) or H-89 (0.1 nmol). But i.t. pre (0.01, 0.1 and 1 noml) or post-treatment (1 noml) with CH had significant suppressive effect on primary thermal hyperalgesia induced by s.c. bee venom injection.4. The roles of spinal PKC and cAMP-PKA intracellular signal pathways in induction and maintenance of the BV-induced primary mechanical hyperalgesiaI.t. pre-treatment with SQ22536 (0.1, 0.5 and 1 nmol) or with H-89 (0.001, 0.01 and 0.1 nmol) had a dose-dependent suppressive effect on primary mechanical hyperalgesia. I.t. post-treatment with SQ22536 at the highest dose used in the pre-treatment group (1 noml) had no significant suppressive effect on primary mechanical hyperalgesia; but i.t. post- treatment with H-89 at the highest dose used in the pre-treatment group (0.1 noml) resulted in significant suppressive effect on primary mechanical hyperalgesia. I.t. pre or post-treatment with CH had no apparent suppressive effect on primary mechanical hyperalgesia.Conclusions1. Co-activation of spinal PKC an...