Different effects of local anesthetics on extracellular signal-regulated kinase phosphorylation in rat dorsal horn neurons.

Local anesthetics, which are widely known to be neuronal voltage-gated Na(+) channel blockers, also affect a variety of other ion channels, N-methyl-d-asparate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-izoxazolepropionic acid (AMPA) receptors. Glutamate, which is released from presynaptic fibers, activates extracellular signal-regulated kinase (ERK) through NMDA and AMPA receptors in spinal dorsal horn neurons. ERK plays a key role in central sensitization, which contributes to the chronicity of pain. We investigated the effects of four representative local anesthetics, lidocaine, tetracaine, levobupivacaine, and ropivacaine on ERK phosphorylation induced by capsaicin, which releases glutamate from presynaptic neurons, NMDA, AMPA, or ionomycin, a calcium ionophore, in dorsal neurons. We observed capsaicin-induced phosphorylation of ERK, which was suppressed by lidocaine, tetracaine, or ropivacaine, but not by levobupivacaine. NMDA-induced phosphorylation of ERK was suppressed by lidocaine, tetracaine, or levobupivacaine, but not by ropivacaine. AMPA-induced phosphorylation of ERK was suppressed by lidocaine or tetracaine, but not by levobupivacaine or ropivacaine. Finally, ionomycin-induced ERK phosphorylation was suppressed by lidocaine, tetracaine, or ropivacaine, but not by levobupivacaine. Our results suggest that local anesthetics contribute to the prevention of the incidence of persistent postsurgical pain with varying intensities and through different mechanisms of action.

Intrathecal endothelin-1 has antinociceptive effects in rat model of postoperative pain.

Endothelin-1 is known to be a potent vasoconstrictor. Administration of endothelin-1 to the central nervous system (CNS) induces antinociceptive effects. Nociceptive stimuli affect dorsal root ganglion (DRG) neurons and neurons/astrocytes/microglia in the dorsal horn of the spinal cord. Surgical incision in the plantar aspect of the rat hindpaw is a model for postoperative pain, and withdrawal thresholds reportedly decrease around the incision. We hypothesized that intrathecal endothelin-1 would have antinociceptive effects in this model, and affect DRG neurons and microglia/neurons in the dorsal horn. Intrathecal endothelin-1 partially restored the withdrawal threshold (which was decreased by plantar incision). BQ-123, and BQ-788 (specific endothelin ET(A)- and ET(B)-receptor antagonists, respectively) attenuated the increase in withdrawal threshold induced by endothelin-1. Phosphorylation of extracellular signal-regulated kinase (ERK) in DRG neurons and microglial activation/ERK phosphorylation in the dorsal horn were observed following the incision. Endothelin-1 decreased the incision-induced increase in the numbers of phosphorylated ERK-positive neurons in DRG and activated microglia in the dorsal horn, without affecting the numbers of phosphorylated ERK-positive neurons in the dorsal horn. BQ-123 or BQ-788 partially suppressed these endothelin-1-induced alterations. Our results show that the pain threshold, which is decreased by surgical stimuli, is partially restored by intrathecal endothelin-1 through both endothelin ET(A)- and ET(B)- receptors in DRG neurons and microglia in the spinal cord. Endothelin-1 administration to the CNS may be worth considering as a new candidate for the treatment of postoperative pain and to mitigate prolonged periods of pain.

Bupivacaine inhibits activation of neuronal spinal extracellular receptor-activated kinase through selective effects on ionotropic receptors.

BACKGROUND: Central terminals of primary nociceptors release neurotransmitters glutamate and substance P, which bind to ionotropic or metabotropic receptors on spinal neurons to induce cellular responses. Extracellular signal-regulated kinases are activated by these receptors and are important modulators of pain at the dorsal horn. The authors investigated these pathways as potential targets for antinociceptive actions of local anesthetics. METHODS: The effects of bupivacaine on the activation of extracellular receptor-activated kinase (phosphorylation to pERK) in rat spinal cord slices, induced by presynaptic release (capsaicin), by presynaptic or postsynaptic ionotropic or metabotropic receptor activation, or by activation of intracellular protein kinase C or protein kinase A and also by a receptor-independent Ca2+ ionophore, were quantitated by immunohistochemistry, counting pERK-positive neurons in the superficial dorsal horn. RESULTS: Capsaicin (3 microm, 10 min)-stimulated pERK was reduced by bupivacaine (IC50 approximately 2 mm, approximately 0.05%), which similarly suppressed pERK induced by the ionotropic glutamate receptors for N-methyl-D-aspartate and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid but not that induced by the metabotropic receptors for glutamate, bradykinin, or substance P. Extracellular receptor-activated kinase activation by the Ca2+ ionophore ionomycin was also sensitive to bupivacaine, but direct activation by protein kinase A or protein kinase C was not. CONCLUSIONS: Bupivacaine inhibits pERK activation resulting from different modes of Ca2+ influx through the plasma membrane. This represents a postsynaptic mechanism of analgesia that occurs in parallel with impulse inhibition during neuraxial blockade.

[Postoperative seizure in an epileptic patient with dentatorubral pallidoluysian atrophy].

A 28-year-old male with dentatorubral pallidoluysian atrophy (DRPLA) was scheduled for evulsion of bone marrow nail after tibia fracture. He was diagnosed as having DRPLA at the age of 12. Although he was receiving anticonvulsants, regular seizures had occurred occasionally and his symptoms were exacerbating. General anesthesia was induced and maintained with intravenous propofol supplemented with fentanyl, nitrous oxide, and oxygen. The operation was performed uneventfully. After the surgery, his breathing was depressed and naloxone was administered to reverse the depression. Thereafter, generalized tonic seizure associated with involuntary movement of the left arm occurred. These symptoms ceased soon after rapid injection of diazepam. Inhaled and intravenous anesthetics have been alleged to have both proconvulsant and anticonvulsant activities in humans. In the present patient with DRPLA, propofol, fentanyl, nitrous oxide, naloxone, and neostigmine administered might be factors, which could have lowered the threshold for seizure activity. Further, patients with DRPLA might have decreased GABA in the basal ganglia, and anesthetics would affect GABA receptors. Thus we should be aware of occurrence of convulsion in DRPLA patients during and after anesthesia.