piperidines and morphine-3-glucuronide

Assess association between UGT2B7 polymorphism -900G>A (rs7438135, also known as -842G>A) with morphine kinetics in preterm newborns undergoing mechanical ventilation.. Thirty-four infants were enrolled in a randomized clinical trial and allocated to rapid sequence intubation with remifentanil (1 µg/kg) or morphine (0.3 mg/kg). The latter group was included in our study.. Morphine plasma concentrations at 20 min post intubation were associated with postnatal age (p=0.017) and UGT2B7 -900G>A (p=0.036). UGT2B7 -900A allele carriers (n=13) had lower morphine levels compared with UGT2B7 -900G/G patients (n=2). Morphine-3-glucuronide and morphine-6-glucuronide plasma concentrations were only found to be associated with gestational and postnatal age. However, -900A allele carriers had a higher morphine-3-glucuronide:morphine metabolic ratio compared with patients genotyped as -900G/G (p=0.005), as determined by linear regression.. Our small pilot study illustrates that in addition to gestational and postnatal age, the UGT2B7 -900G>A polymorphism significantly alters morphine pharmacokinetics in preterm infants.

Topics: Female; Genetic Association Studies; Glucuronosyltransferase; Humans; Infant, Newborn; Morphine; Morphine Derivatives; Obstetric Labor, Premature; Piperidines; Polymorphism, Single Nucleotide; Pregnancy; Randomized Controlled Trials as Topic; Remifentanil

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