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.