PubMed · 9640513
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S Gazzola. 1998. Preparing LET solution.. https://pubmed.ncbi.nlm.nih.gov/9640513/
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Membrane-impermeant quaternary derivatives of lidocaine (QX222 and QX314) block cardiac Na(+) channels when applied from either side of the membrane, but they block neuronal and skeletal muscle channels poorly from the outside. To find the molecular determinants of the cardiac external QX access path, mutations of adult rat skeletal muscle (micro1) and rat heart (rH1) Na(+) channels were studied by two-electrode voltage clamp in Xenopus oocytes. Mutating the micro1 domain I P-loop Y401, which is the critical residue for isoform differences in tetrodotoxin block, to the heart sequence (Y401C) allowed outside QX222 block, but its mutation to brain type (Y401F) showed little block. mu1-Y401C accelerated recovery from block by internal QX222. Block by external QX222 in mu1-Y401C was diminished by chemical modification with methanethiosulfonate ethylammonium (MTSEA) to the outer vestibule or by a double mutant (mu1-Y401C/F1579A), which altered the putative local anesthetic binding site. The reverse mutation in heart rH1-C374Y reduced outside QX314 block and slowed dissociation of internal QX222. Mutation of mu1-C1572 in IVS6 to Thr, the cardiac isoform residue (C1572T), allowed external QX222 block, and accelerated recovery from internal QX222 block, as reported. Blocking efficacy of outside QX222 in mu1-Y401C was more than that in mu1-C1572T, and the double mutant (mu1-Y401C/C1572T) accelerated internal QX recovery more than mu1-Y401C or mu1-C1572T alone. We conclude that the isoform-specific residue (Tyr/Phe/Cys) in the P-loop of domain I plays an important role in drug access as well as in tetrodotoxin binding. Isoform-specific residues in the IP-loop and IVS6 determine outside drug access to an internal binding site.
The nociception by intraplantar (i.pl.) lysophosphatidic acid (LPA) injection was significantly, but partially blocked when mice received intrathecal (i.t.) antisense oligodeoxynucleotide treatment for the vzg-1 type LPA-receptor. The residual LPA-nociception observed under the condition of pertussis toxin-treatment, which is expected to block presynaptic contribution, was abolished by diphenhydramine (i.pl.), an H1-type histamine receptor antagonist. Taking into account that vzg-1 mRNA was detected in the dorsal root ganglion by RT-PCR method, these findings suggest that the LPA-induced nociception is attributed to the mechanism through vzg-1 receptor on nociceptor endings, and to that through unidentified LPA-receptor on peripheral, possibly mast cells.
The aim of the present study was to establish whether contralateral treatment with local anaesthetics reduces nociceptive behaviour in mononeuropathic rats. Contralateral treatment with xylocaine on day 6 and 11 following sciatic nerve ligation increased withdrawal latencies to thermal but not to mechanical stimulation for 3-4 days. Rats who received contralateral treatment with xylocaine on day 6 and 11 showed a reduced autotomy score during the following 6 weeks. To compare ipsilateral and contralateral effects another set of experiments was performed. Rats treated contralaterally on day 11 had a significantly lower autotomy score at week 4 and 6. Our results demonstrate that contralateral treatment with xylocaine reduces nociceptive behaviour in mononeuropathic rats for days or weeks.