Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice.

Morphine-3-glucuronide (M3G), a main metabolite of morphine, has been proposed as a responsible factor when patients present with the neuroexcitatory side effects (allodynia, hyperalgesia, and myoclonus) observed following systemic administration of large doses of morphine. Indeed, both high-dose morphine (60 nmol/5 microl) and M3G (3 nmol/5 microl) elicit allodynia when administered intrathecally (i.t.) into mice. The allodynic behaviors are not opioid receptor mediated. This chapter reviews the potential mechanism of spinally mediated allodynia evoked by i.t. injection of M3G in mice. We discuss a possible presynaptic release of nociceptive neurotransmitters/neuromodulators such as substance P, glutamate, and dynorphin in the primary afferent fibers following i.t. M3G. It is possible to speculate that i.t. M3G injection could activate indirectly both NK(1) receptor and glutamate receptors that lead to the release of nitric oxide (NO) in the dorsal spinal cord. The NO plays an important role in M3G-induced allodynia. The phosphorylation of extracellular signal-regulated protein kinase (ERK) in the dorsal spinal cord evoked via NO/cGMP/PKG pathway contributes to i.t. M3G-induced allodynia. Furthermore, the increased release of NO observed after i.t. injection of M3G activates astrocytes and induces the release of the proinflammatory cytokine, interleukin-1beta. Taken together, these findings suggest that M3G may induce allodynia via activation of NO-ERK pathway, while maintenance of the allodynic response may be triggered by NO-activated astrocytes in the dorsal spinal cord. The demonstration of the cellular mechanisms of neuronal-glial interaction underlying M3G-induced allodynia provides a fruitful strategy for improved pain management with high doses of morphine.

Extracellular signal-regulated kinase (ERK) and nitric oxide synthase mediate intrathecal morphine-induced nociceptive behavior.

Intrathecal (i.t.) administration of morphine at a high dose of 60nmol into the spinal lumbar space in mice produces a severe hindlimb scratching followed by biting and licking. Nitric oxide (NO) is thought to play an important role in signal transduction pathways that enhance nociceptive transmission in the spinal cord. The present study was designed to determine whether high-dose i.t. morphine could influence the activation of the extracellular signal-regulated kinase (ERK), a mitogen-activated protein (MAP) kinase in neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) activation. Both 7-NI and TRIM, selective inhibitors of nNOS, resulted in a dose-dependent inhibition of high-dose i.t. morphine-induced behavior. The selective iNOS inhibitor W1400 in relatively large doses inhibited in a non dose-dependent manner. The i.t. injection of morphine evoked a definite activation of ERK in the lumbar dorsal spinal cord. Behavioral experiments showed that U0126 (0.5-2.5nmol), a MAP kinase-ERK inhibitor, dose-dependently attenuated the behavioral response to i.t. morphine. In mice treated with high-dose morphine, 7-NI was very effective in blocking ERK activation, whereas W1400 had no effect. Taken together, these results suggest that the behavioral response to high-dose i.t. morphine may be triggered by the nNOS-ERK pathway in the dorsal spinal cord.