Antinociceptive actions of honokiol and magnolol on glutamatergic and inflammatory pain

In inflammatory pain, the neurotransmitters (glutamate and serotonin), neuromodulators (substance P) and inflammatory mediators (bradykinin, histamine and prostaglandin) released from the primary afferents and dorsal horn neurons under tissue damage play an important role in eliciting the hyperactivity on nociceptive behaviors [1-5]. A number of evidence has further supported the development of central hyperexcitability and persistent pain relating to the activation of N-methyl-D-aspartate (NMDA) receptors [6]. The glutamatergic system is well known to involve in the inflammatory hyperalgesia, since NMDA and non-NMDA receptor antagonists attenuate the nociceptive behaviors which are associated with inflammatory responses in various animal models [7]. Recently, we have observed that honokiol and magnolol, isolated from the bark of Magnolia officinals [8,9], possess the ability to block the glutamate receptor-mediated intracellular cation signals [10] and inhibit glutamate-induced cell damage [11]. According to the above evidence, it is proposed that honokiol and magnolol may have the potent analgesic activity via blockade of glutamate receptors.Magnolol has been reported to inhibit acetic acid-induced nociceptive response, and to reduce the hind-paw edema induced by carrageenan, compound 48/80, and polymyxin B in mice [12]. Our previous study also demonstrates that honokiol and magnolol block the inflammatory phase of the overt nociception induced by formalin. However, they do not produce analgesia in tail-flick, hot-plate paw-licking and the neurogenic phase of formalin-induced licking response [13]. Thus, we suggest that honokiol and magnolol may not affect the thermal pain, but reduce the inflammatory pain. Therefore, the antinociceptive mechanisms of honokiol and magnolol particularly in inflammatory pain require further investigation.In the present study, we evaluated the antinociceptive actions of honokiol and magnolol on pain behaviors induced by glutamate rec