Transcriptional and posttranslational plasticity and the generation of inflammatory pain

Abstract

Inf lammatory pain manifests as spontaneous pain and pain hypersensitivity. Spontaneous pain ref lects direct activation of specific receptors on nociceptor terminals by inf lammatory mediators. Pain hypersensitivity is the consequence of early posttranslational changes, both in the peripheral terminals of the nociceptor and in dorsal horn neurons, as well as later transcription-dependent changes in effector genes, again in primary sensory and dorsal horn neurons. This inf lammatory neuroplasticity is the consequence of a combination of activity-dependent changes in the neurons and specific signal molecules initiating particular signal-transduction pathways. These pathways phosphorylate membrane proteins, changing their function, and activate transcription factors, altering gene expression. Two distinct aspects of sensory neuron function are changed as a result of these processes, basal sensitivity, or the capacity of peripheral stimuli to evoke pain, and stimulus-evoked hypersensitivity, the capacity of certain inputs to generate prolonged alterations in the sensitivity of the system. Posttranslational changes largely alter basal sensitivity. Transcriptional changes both potentiate the system and alter neuronal phenotype. Potentiation occurs as a result of the up-regulation in the dorsal root ganglion of centrally acting neuromodulators and simultaneously in the dorsal horn of their receptors. This means that the response to subsequent inputs is augmented, particularly those that induce stimulus-induced hypersensitivity. Alterations in phenotype includes the acquisition by A fibers of neurochemical features typical of C fibers, enabling these fibers to induce stimulus-evoked hypersensitivity, something only C fiber inputs normally can do. Elucidation of the molecular mechanisms responsible provides new opportunities for therapeutic approaches to managing inf lammatory pain.Pain is a state-dependent sensory experience. Normally, it is generated only by activation of a specific subset of highthreshold peripheral sensory neurons, the nociceptors, hence nociception-the detection of noxious or tissue-damaging stimuli. Nociception is important for being aware of and reacting to potentially or actually damaging stimuli in the environment. Absence of this capacity, as in individuals with congenital analgesia, results in ongoing tissue damage. Pain is also, of course, a major clinical problem. After inflammation or nerve injury, dramatic alterations in the somatosensory system occur, amplifying responses and increasing sensitivity to peripheral stimuli so that pain can now be activated by normally innocuous or low-intensity stimuli. Clinical pain is an expression, then, of plasticity in the somatosensory system, operating at multiple sites and due to diverse mechanisms. The purpose of this paper is to highlight key features of the plasticity of primary sensory neurons and of the synaptic contacts they make with dorsal horn neurons, the mechanisms that operate to produce this plasticity, and how this relates to t...

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

“…We first tested Src40-49Tat in an inflammatory pain model in which dilute formalin was injected into the rat hindpaw, causing a stereotypic two-phase pattern of behavioral responses 24,25 : phase 1 is independent of NMDARs whereas phase 2 is NMDARdependent 4,26 . We found that pretreating with Src40-49Tat (i.v.…”

“…Multiple mechanisms including increased primary afferent excitability 3 , enhanced transmission in the dorsal horn 1 , changes in gene expression 4 , aberrant neuron-glia interactions 5,6 and neuronal apoptosis 7 are implicated in hypersensitivity in chronic pain models. Abundant pre-clinical evidence indicates that N-methyl-D-aspartate receptor (NMDARs) 8 are critically involved in pain hypersensitivity [9][10][11] .…”

Modulation of I A Currents by Capsaicin in Rat Trigeminal Ganglion Neurons

“…Primary sensory neurons contain several types of voltagegated potassium channels (VGPCs), which include those that activate rapidly and inactivate slowly (I K ) and those that activate and inactivate rapidly (I A ) (Gold et al 1996b;Kostyuk et al 1991;McCleskey and Gold 1999;Petersen et al 1987;Rasband et al 2001;Ricco et al 1996;Seifert et al 2001;Stansfeld et al 1986;Woolf and Costagin 1999;Yoshimura et al 1996). VGPCs of various types are distributed among different types of neurons (Cardenas et al 1995;Djouhri and Lawson 1999;Harper and Lawson 1985).…”

Nociceptors: the sensors of the pain pathway

“…Nociceptors are excitatory neurons and release glutamate as their primary neurotransmitter as well as other components including peptides (e.g., substance P, calcitonin generelated peptide [CGRP], somatostatin) important in both central synaptic signaling and efferent signaling in the skin (13). Invasion of action potentials into the nociceptor soma via the short stem axon (32) can lead to biochemical changes (e.g., phosphorylation and activation of MAPK superfamily of signaling pathways) that ultimately alter gene expression and functional phenotype (33,34). Although it is thought that direct communication between the soma of primary sensory neurons does not occur, vesicle exocytosis is observed in dissociated soma and may influence associated Schwann cells and possibly nearby neurons (35,36).…”