NEUROSCIENCE Cytoskeletal Regulation of Pain Pathways

Inflammatory mediators released in response to tissue injury sensitize primary sensory neurons to pain and thereby lower the pain threshold--a process called hyperalgesia. Both epinephrine and prostaglandin E₂ (PGE₂) produce hyperalgesia by acting through G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) on sensory neurons. PGE₂ produces hyperalgesia through protein kinase A (PKA)-mediated signaling pathways, whereas epinephrine acts through three second messenger systems: PKA, protein kinase C (PKC), and extracellular signal-regulated kinase (ERK). If the tissue has previously been exposed to an inflammatory stimulus, PGE₂-induced hyperalgesia becomes prolonged and involves PKC as well as PKA, a phenomenon called hyperalgesia priming (see Bhave and Gereau). Dina et al. used pharmacological disruption of cytoskeletal elements (microfilaments, microtubules, and intermediate filaments) to investigate the role of the cytoskeleton in hyperalgesia produced by epinephrine and PGE₂. Cytoskeletal disruptors attenuated epinephrine-induced hyperalgesia in rat paws (assessed behaviorally or in vitro through facilitation of a tetrodotoxin-resistant sodium current) but not hyperalgesia in response to PGE₂. In hyperalgesia-primed tissue, PGE₂-stimulated hyperalgesia involved ERK pathways (as well as PKA and PKC pathways) and became sensitive to cytoskeletal disruption. The authors used pharmacological agents to activate PKA, PKC, and ERK independently of GPCRs and found that independent activation of hyperalgesia by PKC and ERK required an intact cytoskeleton, whereas activation of hyperalgesia by PKA did not. Thus, cytoskeletal involvement in specific pathways leading to hyperalgesia differs both at the level of GPCR coupling to effectors and following activation of various kinases. The involvement of the cytoskeleton in hyperalgesia may have implications for the treatment of chronic inflammatory pain.

O. A. Dina, G. C. McCarter, C. de Coupade, J. D. Levine, Role of the sensory neuron cytoskeleton in second messenger signaling for inflammatory pain. Neuron 39, 613-624 (2003). [Online Journal]

G. Bhave, R. W. Gereau IV, Growing pains: The cytoskeleton as a critical regulator of pain plasticity. Neuron 39, 577-579 (2003). [Online Journal]