Roles of peripheral mitogen-activated protein kinases in melittin-induced nociception and hyperalgesia.

Recently, we have reported that melittin, a major toxic peptide of the whole bee venom, plays a central role in production of local inflammation, nociception and hyperalgesia following the experimental honeybee's sting. However, the exact peripheral mechanisms underlying melittin-induced multiple pain-related behaviors are still less characterized. In the present study, we sought to investigate the potential roles of peripheral mitogen-activated protein kinases (MAPKs) in melittin-induced nociception and hyperalgesia by pre- and post-administration of three MAPK inhibitors, namely U0126 (1 mug, 10 mug) for extracellular signal-regulated kinase (ERK), SP600125 (10 mug, 100 mug) for c-Jun N-terminal kinase (JNK) and SB239063 (10 mug, 100 mug) for p38 MAPK, into the local inflamed area of one hind paw of rats. Both pre- and post-treatment with three drugs significantly suppressed the occurrence and maintenance of melittin-evoked persistent spontaneous nociception (PSN) and primary heat hyperalgesia, with little antinociceptive effect on mechanical hyperalgesia. In vehicle-treated group, ipsilateral injection of melittin produced no impact on thermal and mechanical sensitivity of the other hind paw, suggesting no occurrence of contralateral heat and mechanical hyperalgesia in the melittin test. In addition, local administration of each inhibitor into the contralateral hind paw exerted no significant influence on either PSN or heat/mechanical hyperalgesia tested in the primary injured hind paw, excluding the systemically pharmacological effects of the three drugs. Furthermore, local administration of the three compounds in naïve animals, respectively, did not change the basal pain sensitivity to either thermal or mechanical stimuli, suggesting lack of peripherally functional roles of the three MAPK subfamily members in normal pain sensitivity under the physiological state. Taken together, we conclude that activation of peripheral MAPKs, including ERK, JNK and p38, might contribute to the induction and maintenance of persistent ongoing pain and primary heat hyperalgesia in the melittin test. However, they are not likely to be involved in the processing of melittin-induced primary mechanical hyperalgesia, implicating a mechanistic separation between mechanical and thermal hyperalgesia in the periphery.