cyclic-gmp and morphine-3-glucuronide

Morphine with its potent analgesic property has been widely used for the treatment of various types of pain. However, the intrathecal (i.t.) administration of morphine at doses far higher than those required for antinociception exhibited nociceptive-related behaviors consisting of scratching, biting and licking, hyperalgesia, and allodynia in mice. Morphine-3-glucuronide (M3G), one of the major metabolites of morphine, has been found to evoke nociceptive behaviors similar to those after high-dose i.t. morphine. It is plausible that M3G may be responsible for nociception seen after high-dose i.t. morphine treatment. This article reviews the potential mechanism of spinally mediated nociceptive behaviors evoked by i.t. M3G in mice. We discuss the possible presynaptic release of nociceptive neurotransmitters/neuromodulators such as substance P, glutamate, dynorphin, and Leu-enkephalin in the primary afferent fibers following i.t. M3G administration. It is possible to speculate that i.t. M3G could indirectly activate NK1, NMDA, and δ2-opioid receptors that lead to the release of nitric oxide (NO) in the dorsal spinal cord. The major function of NO is the production of cGMP and the activation of protein kinase G (PKG). The NO-cGMP-PKG pathway plays an important role in M3G-induced nociceptive behavior. The phosphorylation of extracellular signal-related kinase (ERK) in the dorsal spinal cord was also evoked via the NO-cGMP-PKG pathway through the activation of δ2-opioid, NK1, and NMDA receptors, contributing to M3G-induced nociceptive behaviors. The demonstration of a neural mechanism underlying M3G-induced nociception provides a pharmacological basis for improved pain management with morphine at high doses.

Topics: Analgesics, Opioid; Animals; Central Nervous System Stimulants; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Humans; Injections, Spinal; Mice; Morphine; Morphine Derivatives; Neurotransmitter Agents; Nitric Oxide; Nociception; Signal Transduction; Substance P; Synapses

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.

Topics: Animals; Astrocytes; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Extracellular Signal-Regulated MAP Kinases; Glutamic Acid; Injections, Spinal; Mice; Morphine Derivatives; Nitric Oxide; Pain; Spinal Cord; Substance P

Intrathecal (i.t.) injection of morphine-3-glucuronide (M3G), a major metabolite of morphine without analgesic actions, produces a severe hindlimb scratching followed by biting and licking in mice. The pain-related behavior evoked by M3G was inhibited dose-dependently by i.t. co-administration of tachykinin NK(1) receptor antagonists, sendide, [D-Phe(7), D-His(9)] substance P(6-11), CP-99994 or RP-67580 and i.t. pretreatment with antiserum against substance P. The competitive NMDA receptor antagonists, D-APV and CPP, the NMDA ion-channel blocker, MK-801 or the competitive antagonist of the polyamine recognition site of NMDA receptor ion-channel complex, ifenprodil, produced inhibitory effects on i.t. M3G-evoked nociceptive response. The NO-cGMP-PKG pathway, which involves the extracellular signal-regulated kinase (ERK), has been implicated as mediators of plasticity in several pain models. Here, we investigated whether M3G could influence the ERK activation in the NO-cGMP-PKG pathway. The i.t. injection of M3G evoked a definite activation of ERK in the lumbar dorsal spinal cord, which was prevented dose-dependently by U0126, a MAP kinase-ERK inhibitor. The selective nNOS inhibitor N(omega)-propyl-l-arginine, the selective iNOS inhibitor W1400, the soluble guanylate cyclase inhibitor ODQ and the PKG inhibitor KT-5823 inhibited dose-dependently the nociceptive response to i.t. M3G. In western blotting analysis, inhibiting M3G-induced nociceptive response using these inhibitors resulted in a significant blockade of ERK activation induced by M3G in the spinal cord. Taken together, these results suggest that activation of the spinal ERK signaling in the NO-cGMP-PKG pathway contributes to i.t. M3G-evoked nociceptive response.

Topics: Analgesics; Animals; Behavior, Animal; Butadienes; Central Nervous System Stimulants; Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Injections, Spinal; Isoindoles; Male; Mice; Mice, Inbred Strains; Morphine Derivatives; Nitric Oxide; Nitriles; Nociceptors; Pain; Peptide Fragments; Piperidines; Pyrrolidonecarboxylic Acid; Receptors, Tachykinin; Specific Pathogen-Free Organisms; Spinal Cord; Stereoisomerism; Substance P