ABSTRACT
The isolectin I-B4 (IB4) binds specifically to a subset of small sensory neurons. We used a conjugate of IB4 and the toxin saporin to examine in vivo the contribution of IB4-binding sensory neurons to nociception. A single dose of the conjugate was injected unilaterally into the sciatic nerve of rats. The treatment resulted in a permanent selective loss of IB4-binding neurons as indicated by histological analysis of dorsal root ganglia, spinal cord, and skin from treated animals. Behavioral measurements showed that 7-10 days after the injection, conjugate-treated rats had elevated thermal and mechanical nociceptive thresholds. However, 21 days post-treatment the nociceptive thresholds returned to baseline levels. These results demonstrate the utility of the IB4-saporin conjugate as a tool for selective cytotoxic targeting and provide behavioral evidence for the role of IB4-binding neurons in nociception. The decreased sensitivity to noxious stimuli associated with the loss of IB4-binding neurons indicates that these sensory neurons are essential for the signaling of acute pain. Furthermore, the unexpected recovery of nociceptive thresholds suggests that the loss of IB4-binding neurons triggers changes in the processing of nociceptive information, which may represent a compensatory mechanism for the decreased sensitivity to acute pain.
Subject(s)
Lectins/metabolism , N-Glycosyl Hydrolases , Neurons, Afferent/metabolism , Nociceptors/physiology , Animals , Cell Count , Immunotoxins/pharmacology , Lectins/pharmacology , Male , Myelin Sheath/drug effects , Neurons, Afferent/cytology , Pain Threshold/drug effects , Plant Proteins/pharmacology , Rats , Rats, Sprague-Dawley , Ribosome Inactivating Proteins, Type 1 , Saporins , Schwann Cells/drug effects , Schwann Cells/metabolism , Sciatic Nerve/cytology , Sciatic Nerve/drug effects , Sciatic Nerve/metabolismABSTRACT
The acid sensing ion channel (ASIC) identified in rat brain and spinal cord is potentially involved in the transmission of acid-induced nociception. We have developed polyclonal antisera against ASIC, and used them to screen rat brain and spinal cord using immunocytochemistry. ASIC-immunoreactivity (-ir) is present in but not limited to the superficial dorsal horn, the dorsal root ganglia (DRG) and the spinal trigeminal nucleus, as well as peripheral nerve fibers. These observations, combined with the disappearance of ASIC-ir following dorsal rhizotomy, suggest localization of ASIC to primary afferents. DRG ASIC-ir co-localizes with substance P (SP) and calcitonin gene-related peptide (CGRP)-ir in small capsaicin-sensitive cell bodies, suggesting that ASIC is poised to play a role in the transduction of noxious stimuli.
Subject(s)
Acids/pharmacology , Ion Channels/drug effects , Neurons, Afferent/chemistry , Pain/physiopathology , Amino Acid Sequence , Animals , Brain/cytology , Brain/drug effects , Brain/metabolism , Calcitonin Gene-Related Peptide/analysis , Female , Guinea Pigs , Male , Molecular Sequence Data , Rats , Rats, Sprague-Dawley , Spinal Cord/cytology , Spinal Cord/drug effects , Spinal Cord/metabolism , Substance P/analysisABSTRACT
Guanidinothiazolecarboxamides (GTCs) are a novel class of antitumor agents found to be systemically active against experimental pulmonary metastases of 3LL Lewis lung carcinoma. A series of substituted benzothiazole GTCs were found to produce enhancement of survival in this model by using 8 days of intraperitoneal dosing initiated 2 days after intravenous tumor challenge. Quantitative structure-activity relationships have been discovered in the GTC series with survival enhancement correlated to substituent parameters. Optimal correlations were found between the probit transform of the drug-induced increased lifespan (ILS) and field and pi parameters. Among the most effective analogues in this series was N-(5-fluorobenzothiazol-2-yl)-2-guanidinothiazole-4-carboxam ide.
