Chronic morphine-mediated upregulation of high mobility group box 1 in the spinal cord contributes to analgesic tolerance and hyperalgesia in rats

Analgesic tolerance and hyperalgesia hinder the long-term utility of opioids. We examined whether spinal high mobility group box 1 (HMGB1) is involved in morphine tolerance and its underlying mechanisms by using a model of repeated intrathecal (i.t.) injections of morphine. The results showed that chronic i.t. morphine exposure led to increased expression of HMGB1, Toll-like receptor 4 (TLR4), and receptor for advanced glycation end products (RAGE) and their mRNAs in the dorsal horn. Morphine challenge also promoted HMGB1 expression and release in cultured spinal neurons, but these effects were inhibited by TAK-242, naloxone (antagonists of TLR4), and TLR4 siRNA. Intrathecal coadministration of morphine with TAK-242 or PDTC (inhibitor of NF-kappa B activation) also reduced HMGB1 expression in the spinal cord. Repeated i.t. coinjections of morphine with glycyrrhizin (GL, an HMGB1 inhibitor) or HMGB1 siRNA prevented reduction of the maximal possible analgesic effect (MPAE) of morphine and alleviated morphine withdrawal-induced hyperalgesia. The established morphine tolerance and hyperalgesia were partially reversed when i.t. injections of GL or HMGB1 antibody started at day 7 of morphine injection. Repeated i.t. injections of morphine with HMGB1 siRNA inhibited the activation of NF-kappa B, but not that of JNK and p38. A single i.t. injection of HMGB1 in naive rats caused pain-related hypersensitivity and reduction in MPAE. Moreover, phosphorylated NF-kappa B p65, TNF-alpha, and IL-1 beta levels in the dorsal horn were upregulated following this treatment, but this upregulation was prevented by coinjection with TAK-242. Together, these results suggest that morphine-mediated upregulation of spinal HMGB1 contributes to analgesic tolerance and hyperalgesia via activation of TLR4/NF-kappa B signaling, and the HMGB1 inhibitor might be a promising adjuvant to morphine in the treatment of intractable pain in the clinic.