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Time perception is an important ability that is related closely to humans' and animals' daily activities. It can be distorted by various emotional states. In human studies, experimental pain has been shown to prolong the perception of time. However, related animal studies are lacking. In this study, we used a temporal bisection task to investigate how acute inflammatory pain (induced by hind-paw formalin injection) and chronic neuropathic pain [induced by spinal nerve ligation (SNL)] affected time perception in rats. Rats were trained to recognize "short" (1200-ms) and "long" (2400-ms) anchor-duration pure tones and were rewarded for corresponding lever presses. During testing, rats perceived a series of intermediate-duration and anchor-duration pure tones, and selected levers corresponding to the "short" and "long" tones. After formalin injection, rats gave more "long" lever-press responses than after saline injection. The point of subjective equality after formalin injection also increased, suggesting that formalin-induced acute pain extended time perception. In contrast, rats that had undergone SNL gave fewer "long" lever-press responses compared with the sham surgery group. This animal study suggests that formalin-induced pain and neuropathic pain may have different effects on time perception.
Learn More >Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes (FPS) and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8-10. Pain and depressive-like behavior were measured over 14 days and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain, and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females versus males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. While low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females.
Learn More >Oxidative stress is an important driver of neuropathic painDimethyl fumarate activates nuclear factor erythroid 2-related factor 2, increasing the expression of multiple antioxidant genes WHAT THIS ARTICLE TELLS US THAT IS NEW: Using a rat model of nerve injury, both male and female animals displayed reduced mechanical and nociceptive sensitization when given dimethyl fumarateDimethyl fumarate administration increased superoxide dismutase activity while decreasing cytokine expression and improving mitochondrial bioenergetics BACKGROUND:: Available treatments for neuropathic pain have modest efficacy and significant adverse effects, including abuse potential. Because oxidative stress is a key mechanistic node for neuropathic pain, the authors focused on the master regulator of the antioxidant response-nuclear factor erythroid 2-related factor 2 (NFE2L2; Nrf2)-as an alternative target for neuropathic pain. The authors tested whether dimethyl fumarate (U.S. Food and Drug Administration-approved treatment for multiple sclerosis) would activate NFE2L2 and promote antioxidant activity to reverse neuropathic pain behaviors and oxidative stress-dependent mechanisms.
Learn More >The mechanisms supporting bone cancer pain are incompletely understoodStress of the endoplasmic reticulum has been implicated in supporting pain in some chronic pain states WHAT THIS ARTICLE TELLS US THAT IS NEW: Using a murine model of bone cancer pain, it was observed that tumor growth was associated with the spinal production of inflammatory mediators and increased expression of endoplasmic reticulum stress markersThe pharmacologic inhibition of endoplasmic reticulum stress reduced pain-related behaviors and the production of inflammatory mediators in spinal tissue BACKGROUND:: Prolonged endoplasmic reticulum stress has been identified in various diseases. Inflammatory mediators, which have been shown to induce endoplasmic reticulum stress in several studies, have been suggested to serve as the important modulators in pain development. In this study, the authors hypothesized that the endoplasmic reticulum stress triggered by inflammatory mediators contributed to pain development.
Learn More >Migraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at intracortical synapses in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory balance in specific circuits is a key pathogenic mechanism. Here, we investigated the thalamocortical (TC) feed-forward inhibitory microcircuit in FHM1 mice of both sexes carrying a gain-of-function mutation in Ca2.1. We show that TC synaptic transmission in somatosensory cortex is enhanced in FHM1 mice. Due to similar gain-of-function of TC excitation of layer 4 excitatory and fast-spiking inhibitory neurons elicited by single thalamic stimulations, neither the excitatory-inhibitory balance nor the integration time window set by the TC feed-forward inhibitory microcircuit were altered in FHM1 mice. However, during repetitive thalamic stimulation, the typical shift of the excitatory-inhibitory balance towards excitation and the widening of the integration time window were both smaller in FHM1 compared to wild-type mice, revealing a dysregulation of the excitatory-inhibitory balance, whereby the balance is relatively skewed towards inhibition. This is due to an unexpected differential effect of the FHM1 mutation on short-term synaptic plasticity at TC synapses on cortical excitatory and fast-spiking inhibitory neurons. Our findings point to enhanced transmission of sensory, including trigeminovascular nociceptive, signals from thalamic nuclei to cortex and TC excitatory-inhibitory imbalance as mechanisms that may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine.Migraine is a complex brain disorder, characterized by attacks of unilateral headache and by global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. Here we provide insights into these mechanisms by investigating thalamocortical (TC) synaptic transmission and the function of the TC feed-forward inhibitory microcircuit in a mouse model of a rare monogenic migraine. This microcircuit is critical for gating information flow to cortex and for sensory processing. We reveal increased TC transmission and dysregulation of the cortical excitatory-inhibitory balance set by the TC feed-forward inhibitory microcircuit, whereby the balance is relatively skewed towards inhibition during repetitive thalamic activity. These alterations may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine.
Learn More >Rapid conduction of nerve impulses is critical in life and relies on action potential (AP) leaps through the nodes of Ranvier (NRs) along myelinated nerves. While NRs are the only sites where APs can be regenerated during nerve conduction on myelinated nerves, ion channel mechanisms underlying the regeneration and conduction of APs at mammalian NRs remain incompletely understood. Here, we show that TREK-1 and TRAAK, the thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels, are clustered at NRs of rat trigeminal Aβ-afferent nerves with a density over 3,000-fold higher than that on their somas. These K2P channels, but not voltage-gated K channels as in other parts of nerves, are required for rapid AP repolarization at the NRs. Furthermore, these channels permit high-speed and high-frequency AP conduction along the myelinated afferent nerves, and loss of function of these channels at NRs retards nerve conduction and impairs sensory behavioral responses in animals.
Learn More >Nerve Growth Factor (NGF) is a key mediator of nociception, acting during development and differentiation of dorsal root ganglia (DRGs) neurons, and on adult DRG neuron sensitization to painful stimuli. NGF has also central actions in the brain, where it regulates the phenotypic maintenance of cholinergic neurons. The physiological function of NGF as a pain mediator is altered in patients with Hereditary Sensory and Autonomic Neuropathy V (HSAN V), caused by the 661C>T transition in the gene, resulting in the R100W missense mutation in mature NGF. Homozygous HSAN V patients present with congenital pain insensitivity, but are cognitively normal. This led us to hypothesize that the R100W mutation may differentially affect the central and peripheral actions of NGF. To test this hypothesis and provide a mechanistic basis to the HSAN V phenotype, we generated transgenic mice harbouring the human 661C>T mutation in the gene, and studied both males and females. We demonstrate that heterozygous NGF mice display impaired nociception. DRG neurons of NGF mice are morphologically normal, with no alteration in the different DRG subpopulations, whereas skin innervation is reduced. The NGF protein has reduced capability to activate pain-specific signalling, paralleling its reduced ability to induce mechanical allodynia. Surprisingly, however, NGF mice, unlike heterozygous mNGF mice, show no learning nor memory deficits, despite a reduction in secretion and brain levels of NGF. The results exclude haploinsufficiency of NGF as a mechanistic cause for heterozygous HSAN V mice, and demonstrate a specific effect of the R100W mutation on nociception.The R100W mutation in Nerve Growth Factor (NGF) causes Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), a rare disease characterized by impaired nociception, even in apparently clinically silent heterozygotes. For the first time, we generated and characterized heterozygous knock-in mice carrying the human, R100W-mutated allele (NGF). Mutant mice have normal nociceptor populations which, however, display decreased activation of pain transduction pathways. NGF interferes with peripheral and central NGF bioavailability, but this does not impact on central nervous system function, as demonstrated by normal learning and memory, in contrast with heterozygous NGF knock-out mice. Thus, a point mutation allows to split neurotrophic and pronociceptive functions of NGF, with interesting implications for treatment of chronic pain.
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