Chronic, often intractable, pain is caused by neuropathic conditions such as traumatic peripheral nerve injury (PNI) and spinal cord injury (SCI). These conditions are associated with alterations in ...gene and protein expression correlated with functional changes in somatosensory neurons having cell bodies in dorsal root ganglia (DRGs). Most studies of DRG transcriptional alterations have utilized PNI models where axotomy-induced changes important for neural regeneration may overshadow changes that drive neuropathic pain. Both PNI and SCI produce DRG neuron hyperexcitability linked to pain, but contusive SCI produces little peripheral axotomy or peripheral nerve inflammation. Thus, comparison of transcriptional signatures of DRGs across PNI and SCI models may highlight pain-associated transcriptional alterations in sensory ganglia that do not depend on peripheral axotomy or associated effects such as peripheral Wallerian degeneration. Data from our rat thoracic SCI experiments were combined with meta-analysis of published whole-DRG RNA-seq datasets from prominent rat PNI models. Striking differences were found between transcriptional responses to PNI and SCI, especially in regeneration-associated genes (RAGs) and long noncoding RNAs (lncRNAs). Many transcriptomic changes after SCI also were found after corresponding sham surgery, indicating they were caused by injury to surrounding tissue, including bone and muscle, rather than to the spinal cord itself. Another unexpected finding was of few transcriptomic similarities between rat neuropathic pain models and the only reported transcriptional analysis of human DRGs linked to neuropathic pain. These findings show that DRGs exhibit complex transcriptional responses to central and peripheral neural injury and associated tissue damage. Although only a few genes in DRG cells exhibited similar changes in expression across all the painful conditions examined here, these genes may represent a core set whose transcription in various DRG cell types is sensitive to significant bodily injury, and which may play a fundamental role in promoting neuropathic pain.
Studies using rodent models of neuropathic pain use sham surgery control procedures that cause deep tissue damage. Sham surgeries would thus be expected to induce potentially long-lasting ...postsurgical pain, but little evidence for such pain has been reported. Operant tests of voluntary behavior can reveal negative motivational and cognitive aspects of pain that may provide sensitive tools for detecting pain-related alterations. In a previously described operant mechanical conflict test involving lengthy familiarization and training, rodents freely choose to either escape from a brightly lit chamber by crossing sharp probes or refuse to cross. Here, we describe a brief (2-day) mechanical conflict protocol that exploits rats' innate exploratory response to a novel environment to detect persistently enhanced pain-avoidance behavior after sham surgeries for 2 neural injury models: thoracic spinal cord injury and chronic constriction injury of the sciatic nerve. Pitting the combined motivations to avoid the bright light and to explore the novel device against pain from crossing noxious probes disclosed a conflicting, hyperalgesia-related reluctance to repeatedly cross the probes after injury. Rats receiving standard sham surgeries demonstrated enhanced pain-like avoidance behavior compared with naive controls, and this behavior was similar to that of corresponding chronic constriction injury or spinal cord injury rats weeks or months after injury. In the case of sham surgery for spinal cord injury, video analysis of voluntary exploratory behavior directed at the probes revealed enhanced forepaw withdrawal responses. These findings have important implications for preclinical investigations into behavioral alterations and physiological mechanisms associated with postsurgical and neuropathic pain.
Retinoids are structurally related derivatives of vitamin A and are required for normal vision as well as cell proliferation and differentiation. Clinically, retinoids are effective in treating many ...skin disorders and cancers. Application of retinoids evokes substantial irritating side effects, including pain and inflammation; however, the precise mechanisms accounting for the sensory hypersensitivity are not understood. Here we show that both naturally occurring and synthetic retinoids activate recombinant or native transient receptor potential channel vanilloid subtype 1 (TRPV1), an irritant receptor for capsaicin, the pungent ingredient of chili peppers. In vivo, retinoids produced pain-related behaviors that were either eliminated or significantly reduced by genetic or pharmacological inhibition of TRPV1 function. These findings identify TRPV1 as an ionotropic receptor for retinoids and provide cellular and molecular insights into retinoid-evoked hypersensitivity. These findings also suggest that selective TRPV1 antagonists are potential therapeutic drugs for treating retinoid-induced sensory hypersensitivity.
A majority of people who have sustained spinal cord injury (SCI) experience chronic pain after injury, and this pain is highly resistant to available treatments. Contusive SCI in rats at T10 results ...in hyperexcitability of primary sensory neurons, which contributes to chronic pain. KCNQ channels are widely expressed in nociceptive dorsal root ganglion (DRG) neurons, are important for controlling their excitability, and their activation has proven effective in reducing pain in peripheral nerve injury and inflammation models. The possibility that activators of KCNQ channels could be useful for treating SCI-induced chronic pain is strongly supported by the following findings. First, SCI, unlike peripheral nerve injury, failed to decrease the functional or biochemical expression of KCNQ channels in DRG as revealed by electrophysiology, real-time quantitative polymerase chain reaction, and Western blot; therefore, these channels remain available for pharmacological targeting of SCI pain. Second, treatment with retigabine, a specific KCNQ channel opener, profoundly decreased spontaneous activity in primary sensory neurons of SCI animals both in vitro and in vivo without changing the peripheral mechanical threshold. Third, retigabine reversed SCI-induced reflex hypersensitivity, adding to our previous demonstration that retigabine supports the conditioning of place preference after SCI (an operant measure of spontaneous pain). In contrast to SCI animals, naïve animals showed no effects of retigabine on reflex sensitivity or conditioned place preference by pairing with retigabine, indicating that a dose that blocks chronic pain-related behavior has no effect on normal pain sensitivity or motivational state. These results encourage the further exploration of U.S. Food and Drug Administration-approved KCNQ activators for treating SCI pain, as well as efforts to develop a new generation of KCNQ activators that lack central side effects.
The molecular mechanisms of chronic pain are poorly understood and effective mechanism-based treatments are lacking. Here, we report that mice lacking adenosine deaminase (ADA), an enzyme necessary ...for the breakdown of adenosine, displayed unexpected chronic mechanical and thermal hypersensitivity due to sustained elevated circulating adenosine. Extending from Ada−/− mice, we further discovered that prolonged elevated adenosine contributed to chronic pain behaviors in two additional independent animal models: sickle cell disease mice, a model of severe pain with limited treatment, and complete Freund’s adjuvant paw-injected mice, a well-accepted inflammatory model of chronic pain. Mechanistically, we revealed that activation of adenosine A2B receptors on myeloid cells caused nociceptor hyperexcitability and promoted chronic pain via soluble IL-6 receptor trans-signaling, and our findings determined that prolonged accumulated circulating adenosine contributes to chronic pain by promoting immune-neuronal interaction and revealed multiple therapeutic targets.
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•Adenosine (Ado) deaminase deficient mice displayed chronic pain•Excess Ado signaling via ADORA2B promotes chronic pain in three distinct models•ADORA2B activation induces immunoneuronal interaction and promotes chronic pain•IL-6 trans-signaling underlies ADORA2B-induced prolonged hypersensitive nociception
Hu et al. show that prolonged increase in plasma adenosine activates ADORA2B on myeloid cells, leading to an increase in circulating IL-6 and sIL-6R. The IL-6/sIL-6R complex trans-activates gp130 on DRG cells, leading to STAT3 phosphorylation and induction of neuronal TRPV1 expression that results in increased sensitivity and chronic pain.
Injury to sensory neurons causes an increase in the excitability of these cells leading to enhanced action potential generation and a lowering of spike threshold. This type of sensory neuron ...plasticity occurs across vertebrate and invertebrate species and has been linked to the development of both acute and persistent pain. Injury-induced plasticity in sensory neurons relies on localized changes in gene expression that occur at the level of mRNA translation. Many different translation regulation signalling events have been defined and these signalling events are thought to selectively target subsets of mRNAs. Recent evidence from mice suggests that the key signalling event for nociceptor plasticity is mitogen-activated protein kinase-interacting kinase (MNK) -mediated phosphorylation of eukaryotic translation initiation factor (eIF) 4E. To test the degree to which this is conserved in other species, we used a previously described sensory neuron plasticity model in
. We find, using a variety of pharmacological tools, that MNK signalling is crucial for axonal hyperexcitability in sensory neurons from
. We propose that MNK-eIF4E signalling is a core, evolutionarily conserved, signalling module that controls nociceptor plasticity. This finding has important implications for the therapeutic potential of this target, and it provides interesting clues about the evolutionary origins of mechanisms important for pain-related plasticity. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
How an octopus performs complex movements of its eight sucker-studded arms without entanglement has been a mystery. A new study has found that self-recognition of the octopus’s skin by its suckers ...inhibits reflexive grasping of its own arms, simplifying the mechanisms needed to generate intricate arm behavior.
How an octopus performs complex movements of its eight sucker-studded arms without entanglement has been a mystery. A new study has found that self-recognition of the octopus’s skin by its suckers inhibits reflexive grasping of its own arms, simplifying the mechanisms needed to generate intricate arm behavior.
Survivable injuries are a common yet costly experience. The ability to sense and respond to noxious stimuli is an almost universal trait, and prolonged behavioral alterations, including sensitization ...to touch and other stimuli, may function to ameliorate fitness costs associated with injury. Cephalopods can modify their behavior by learned association with noxious electric shock, but non-associative alterations of behavioral responses after tissue injury have not been studied. The aim of this study was to make the first systematic investigations in any cephalopod of behavioral responses and alterations elicited by explicit, minor injury. By testing responsiveness in the longfin squid, Loligo pealeii, to the approach and contact of an innocuous filament applied to different parts of the body both before and after injury to the distal third of one arm, we show that a cephalopod expresses behavioral alterations persisting for at least 2 days after injury. These alterations parallel forms of nociceptive plasticity in other animals, including general and site-specific sensitization to tactile stimuli. A novel finding is that hyper-responsiveness after injury extends to visual stimuli. Injured squid are more likely to employ crypsis than escape in response to an approaching visual stimulus shortly after injury, but initiate escape earlier and continue escape behaviors for longer when tested from 1 to 48 h after injury. Injury failed to elicit overt wound-directed behavior (e.g. grooming) or change hunting success. Our results show that long-lasting nociceptive sensitization occurs in cephalopods, and suggest that it may function to reduce predation risk after injury.
Mechanisms underlying chronic pain that develops after spinal cord injury (SCI) are incompletely understood. Most research on SCI pain mechanisms has focused on neuronal alterations within pain ...pathways at spinal and supraspinal levels associated with inflammation and glial activation. These events might also impact central processes of primary sensory neurons, triggering in nociceptors a hyperexcitable state and spontaneous activity (SA) that drive behavioral hypersensitivity and pain. SCI can sensitize peripheral fibers of nociceptors and promote peripheral SA, but whether these effects are driven by extrinsic alterations in surrounding tissue or are intrinsic to the nociceptor, and whether similar SA occurs in nociceptors in vivo are unknown. We show that small DRG neurons from rats (Rattus norvegicus) receiving thoracic spinal injury 3 d to 8 months earlier and recorded 1 d after dissociation exhibit an elevated incidence of SA coupled with soma hyperexcitability compared with untreated and sham-treated groups. SA incidence was greatest in lumbar DRG neurons (57%) and least in cervical neurons (28%), and failed to decline over 8 months. Many sampled SA neurons were capsaicin sensitive and/or bound the nociceptive marker, isolectin B4. This intrinsic SA state was correlated with increased behavioral responsiveness to mechanical and thermal stimulation of sites below and above the injury level. Recordings from C- and Aδ-fibers revealed SCI-induced SA generated in or near the somata of the neurons in vivo. SCI promotes the entry of primary nociceptors into a chronic hyperexcitable-SA state that may provide a useful therapeutic target in some forms of persistent pain.
Molluscs have proven to be invaluable models for basic neuroscience research, yielding fundamental insights into a range of biological processes involved in action potential generation, synaptic ...transmission, learning, memory, and, more recently, nociceptive biology. Evidence suggests that nociceptive processes in primary nociceptors are highly conserved across diverse taxa, making molluscs attractive models for biomedical studies of mechanisms that may contribute to pain in humans but also exposing them to procedures that might produce painlike sensations. We review the physiology of nociceptors and behavioral responses to noxious stimulation in several molluscan taxa, and discuss the possibility that nociception may result in painlike states in at least some molluscs that possess more complex nervous systems. Few studies have directly addressed possible emotionlike concomitants of nociceptive responses in molluscs. Because the definition of pain includes a subjective component that may be impossible to gauge in animals quite different from humans, firm conclusions about the possible existence of pain in molluscs may be unattainable. Evolutionary divergence and differences in lifestyle, physiology, and neuroanatomy suggest that painlike experiences in molluscs, if they exist, should differ from those in mammals. But reports indicate that some molluscs exhibit motivational states and cognitive capabilities that may be consistent with a capacity for states with functional parallels to pain. We therefore recommend that investigators attempt to minimize the potential for nociceptor activation and painlike sensations in experimental invertebrates by reducing the number of animals subjected to stressful manipulations and by administering appropriate anesthetic agents whenever practicable, welfare practices similar to those for vertebrate subjects.
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