anisomycin and Pain

Neuronal proton-gated acid-sensing ion channels (ASICs) participate in the detection of tissue acidosis, a phenomenon often encountered in painful pathologic diseases. Such conditions often involve in parallel the activation of various signaling pathways such as mitogen activated protein kinases (MAPKs) that ultimately leads to phenotype modifications of sensory neurons. Here, we identify one member of the MAPKs, c-Jun N-terminal kinase (JNK), as a new post-translational positive regulator of ASICs in rodent sensory neurons. Recombinant H

Topics: Acid Sensing Ion Channels; Amino Acid Sequence; Animals; Anisomycin; Anthracenes; Cells, Cultured; Ganglia, Spinal; HEK293 Cells; Humans; JNK Mitogen-Activated Protein Kinases; Male; Mice; Mice, Inbred C57BL; Pain; Protein Processing, Post-Translational; Protein Synthesis Inhibitors; Rats; Rats, Wistar

Hyperalgesia arising from sensitization of pain relays in the spinal dorsal horn shares many mechanistic and phenotypic parallels with memory formation. We discovered that mechanical hyperalgesia could be rendered labile and reversible in mice after reactivation of spinal pain pathways in a process analogous to memory reconsolidation. These findings reveal a previously unknown regulatory mechanism underlying hyperalgesia and demonstrate the existence of reconsolidation-like processes in a sensory system.

Topics: Animals; Anisomycin; Capsaicin; Central Nervous System Sensitization; Disease Models, Animal; Hyperalgesia; Male; Memory; Mice; Mice, Inbred C57BL; Pain; Posterior Horn Cells; Protein Synthesis Inhibitors; Sensory System Agents; Spinal Cord

Many studies have demonstrated that premenopausal women are at increased risk for various pain disorders. Pain-sensing neurons, termed "nociceptors," in the trigeminal ganglia (TG) and dorsal root ganglia (DRG) express receptors for inflammatory mediators and noxious physical stimuli and transmit signals for central processing of pain sensation. Estrogen receptors (ERs) are also expressed on nociceptors in the TG and DRG, and there is ample literature to suggest that activation of ERs can influence pain mechanisms. However, the mechanism for ER modulation of nociceptor activity is incompletely understood. The aim of this study was to characterize the effect of 17β-estradiol (17β-E(2)) on signaling of the inflammatory mediator bradykinin (BK) in primary cultures of rat sensory neurons and a behavioral model of thermal allodynia in rats. Here, we show that exposure to 17β-E(2) rapidly (within 15 min) enhanced responses to BK in vitro and in vivo. The 17β-E(2)-mediated enhancement of BK signaling was not blocked by the transcription inhibitor anisomycin and was mediated by a membrane-associated ER. The effect of 17β-E(2) to enhance BK responses required activation of β1-containing, RGD-binding integrins. These data show that 17β-E(2) rapidly enhances inflammatory mediator responses both in vitro and in vivo and suggest that 17β-E(2) acting at primary sensory pain neurons may participate in regulating the sensitivity of women to painful stimuli.

Topics: Animals; Anisomycin; Behavior, Animal; Bradykinin; Cells, Cultured; Estradiol; Female; Ganglia, Spinal; Inositol Phosphates; Integrins; Male; Nerve Endings; Nucleic Acid Synthesis Inhibitors; Pain; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells; Signal Transduction; Trigeminal Ganglion; Type C Phospholipases