Linda Watkins

Linda Watkins
University of Colorado Boulder | CUB

About

588
Publications
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58,456
Citations

Publications

Publications (588)
Article
Full-text available
Up to 92% of patients suffering from multiple sclerosis (MS) experience pain, most without adequate treatment, and many report pain long before motor symptoms associated with MS diagnosis. In the most commonly studied rodent model of MS, experimental autoimmune encephalomyelitis (EAE), motor impairments/disabilities caused by EAE can interfere with...
Article
Microglia shape synaptic connections among neurons of the central nervous system (CNS) during development and adulthood. In this review, the actions by which they facilitate pruning, refinement, and new synaptic development throughout the lifespan are considered, along with the molecular mechanisms by which neurons and microglia communicate to guid...
Article
Animal and human studies have shown that exercise prior to nerve injury prevents later chronic pain, but the mechanisms of such preconditioning remain elusive. Given that exercise acutely increases formation of free radicals, triggering antioxidant compensation, we hypothesized that voluntary running preconditioning would attenuate neuropathic pain...
Conference Paper
Prolonged cognitive deficits following surgery are associated with higher risk for mortality and dementia in the elderly. Mechanisms driving susceptibility for these persistent deficits are not well understood. Even less is understood about how post-operative opioids impact post-surgical cognition. Here we report that treatment with post-surgical m...
Conference Paper
Background: POCD is a surgical complication characterized by confusion, executive function deficits & memory impairment. Persistent POCD is experienced by some older individuals & is associated with increased risk of dementia. We've shown that morphine treatment exaggerates & prolongs surgery-induced inflammation, leading to persistent POCD lasting...
Preprint
Full-text available
Animal and human studies have shown that exercise prior to nerve injury prevents later chronic pain, but the mechanisms of such preconditioning remain elusive. Given that exercise acutely increases formation of free radicals, triggering antioxidant compensation, we hypothesized that voluntary running preconditioning would attenuate neuropathic pain...
Article
Spinal cord injury (SCI) elicits chronic pain in 65% of individuals. In addition, SCI afflicts an increasing number of aged individuals, and those with SCI are predisposed to shorter lifespan. Our group previously identified that deletion of the microRNA miR-155 reduced neuroinflammation and locomotor deficits after SCI. Here, we hypothesized that...
Article
Insights into T cell form, function, and dysfunction are rapidly evolving. T cells have remarkably varied effector functions including protecting the host from infection, activating cells of the innate immune system, releasing cytokines and chemokines, and heavily contributing to immunological memory. Under healthy conditions, T cells orchestrate a...
Article
Full-text available
Nicotine is the principal alkaloid of tobacco often manufactured into cigarettes and belongs to a highly addictive class of drugs. Nicotine attenuates the neuroinflammation induced by microglial activation. However, the molecular target(s) underlying anti-inflammatory action of nicotine has not been fully understood. Considering the psychoactive su...
Article
Full-text available
Chronic pain is an unpleasant and debilitating condition that is often poorly managed by existing therapeutics. Reciprocal interactions between the nervous system and the immune system have been recognized as playing an essential role in the initiation and maintenance of pain. In this review, we discuss how neuroimmune signaling can contribute to p...
Article
Neuropathic pain is a major symptom of multiple sclerosis (MS) with up to 92% of patients reporting bodily pain, and 85% reporting pain severe enough to cause functional disability. None of the available therapeutics target MS pain. Toll-like receptors 2 and 4 (TLR2/TLR4) have emerged as targets for treating a wide array of autoimmune disorders, in...
Article
Post-operative cognitive dysfunction (POCD) is the collection of impaired cognitive symptoms, lasting days to months, experienced by individuals following a surgery. Persistent POCD is most commonly experienced by older individuals and is associated with a greater vulnerability to developing Alzheimer’s disease, but the underlying mechanisms are no...
Article
Multiple sclerosis (MS) is associated with burdensome memory impairments. Preclinical literature suggests that these impairments are linked to neuroinflammation. Previously, we have shown that toll-like receptor 4 (TLR4) antagonists, such as (+)-naltrexone [(+)-NTX], block neuropathic pain and associated spinal inflammation in rats. Here we extend...
Article
The proinflammatory cytokine interleukin (IL)-1β plays a pivotal role in the behavioral manifestations (i.e., sickness) of the stress response. Indeed, exposure to acute and chronic stressors induces the expression of IL-1β in stress-sensitive brain regions. Thus, it is typically presumed that exposure to stressors induces the extra-cellular releas...
Article
Osteoarthritis results in chronic pain and loss of function. Proinflammatory cytokines create both osteoarthritis pathology and pain. Current treatments are poorly effective, have significant side effects, and have not targeted the cytokines central to osteoarthritis development and maintenance. Interleukin-10 is an anti-inflammatory cytokine that...
Article
The present series of studies examine the impact of systemically administered therapeutics on peripheral nerve injury (males; unilateral sciatic chronic constriction injury [CCI])‐induced suppression of voluntary wheel running, across weeks after dosing cessation. Following CCI, active phase running distance and speed are suppressed throughout the...
Article
Prior exposure to acute and chronic stressors potentiates the neuroinflammatory and microglial pro-inflammatory response to subsequent immune challenges suggesting that stressors sensitize or prime microglia. Stress-induced priming of the NLRP3 inflammasome has been implicated in this priming phenomenon, however the duration/persistence of these ef...
Article
Morphine-induced alterations in sphingolipid metabolism in the spinal cord and increased formation of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) have been implicated in the development of morphine-induced hyperalgesia (OIH; increased pain sensitivity) and antinociceptive tolerance. These adverse effects hamper opioid use fo...
Article
Circadian rhythms are ∼24 h fluctuations in physiology and behavior that are synchronized with the light-dark cycle. The circadian system ensures homeostatic balance by regulating multiple systems that respond to environmental stimuli including stress systems. In rats, acute exposure to a series of uncontrollable tailshocks (inescapable stress, IS)...
Article
There is growing interest in drug repositioning to find new therapeutic indications for drugs already approved for use in people. Lovastatin is an FDA approved drug that has been used clinically for over a decade as a lipid-lowering medication. While lovastatin is classically considered to act as a hydroxymethylglutaryl (HMG)-CoA reductase inhibito...
Article
Methamphetamine (METH) is a globally abused, highly addictive stimulant. While investigations of the rewarding and motivational effects of METH have focused on neuronal actions, increasing evidence suggests that METH can also target microglia, the innate immune cells of the central nervous system, causing release of proinflammatory mediators and th...
Article
Opioids are widely prescribed for chronic pain, including neuropathic pain despite growing evidence of long-term harm. Previous preclinical studies have documented exacerbation of nociceptive hypersensitivity, including that induced by peripheral nerve injury, by morphine. The present series of behavioral studies sought to replicate and extend our...
Article
Deregulation of innate immune TLR4 signaling contributes to various diseases including neuropathic pain and drug addiction. Naltrexone is one of the rare TLR4 antagonists with good blood-brain barrier permeability and showing no stereoselectivity for TLR4. By linking 2 naltrexone units through a rigid pyrrole spacer, the bivalent ligand norbinaltor...
Article
Full-text available
Exposure to stressors primes neuroinflammatory responses to subsequent immune challenges and stress-induced glucocorticoids (GCs) play a mediating role in this phenomenon of neuroinflammatory priming. Recent evidence also suggests that the alarmin high-mobility group box-1 (HMGB1) and the microglial checkpoint receptor CD200R1 serve as proximal mec...
Article
Advanced age is a major risk factor for developing postoperative cognitive dysfunction (POCD). Age-related neuroinflammatory “priming” may contribute to POCD: peripheral immune stimuli (e.g., infection or surgery) cause exaggerated pro-inflammatory responses in the aged brain that can elicit pathology. Exposure to micro-organisms with immunoregulat...
Article
Spinal cord injury (SCI) can disrupt many physiological functions. The circadian system helps maintain homeostasis throughout the body by regulating daily rhythms in physiology and behavior. Circadian rhythms likely exist in all cell throughout the body, yet whether SCI alters daily rhythms remains under-studied. Here, we hypothesized that SCI in r...
Article
Approximately half of individuals suffering from multiple sclerosis (MS) express cognitive deficits in the form of memory impairments. Previously we have shown that administration of toll-like 2/4 (TLR2/4) antagonists such as (+)-naltrexone [(+)-NTX] block neuropathic pain and associated spinal inflammation in rats. In this study, we examined the e...
Article
Glucocorticoids (GCs) have universally been considered anti-inflammatory. However, mounting evidence now demonstrates that GCs can exert paradoxical effects on innate immune function. In the context of stress exposure, GCs have been found to mediate stress-induced priming of neuroinflammatory responses to subsequent immune challenges. Recent eviden...
Article
Exposure to stressors disrupts homeostasis and results in the release of stress hormones including glucocorti-coids, epinepherine and norepinepherine. Interestingly, stress also has profound affects on microglia, which are tissue-resident macrophages in the brain parenchyma. Microglia express a diverse array of receptors, which also allows them to...
Article
Spinal cord injury (SCI) perturbs many physiological systems. The circadian system helps maintain homeostasis throughout the body by synchronizing physiological and behavioral functions to predictable daily events. Whether disruption of these coordinated daily rhythms contributes to SCI-associated pathology remains understudied. Here, we hypothesiz...
Article
Full-text available
Spinal cord injury (SCI) dysregulates metabolic homeostasis. Metabolic homeostasis is optimized across the day by the circadian system. Despite the prevalence of metabolic pathologies after SCI, post-SCI circadian regulation of metabolism remains understudied. Here, we hypothesized that SCI in rats would disrupt circadian regulation of key metaboli...
Article
Neuropathic pain is a widespread problem which remains poorly managed by currently available therapeutics. Peripheral nerve injury and inflammation leads to changes at the nerve injury site, including activation of resident and recruited peripheral immune cells, that lead to neuronal central sensitization and pain amplification. The present series...
Article
In modern 24 h society, circadian disruption is pervasive, arising from night shift work, air travel across multiple time zones, irregular sleep schedules, and exposure to artificial light at night. Disruption of the circadian system is associated with many adverse health consequences, including mood disorders. Here we investigate whether inducing...
Article
Full-text available
Neuroinflammatory processes promote a constellation of neurochemical and hormonal changes resulting in profound effects on motivational states (anhedonia), mood (depression and anxiety disorders), and cognitive function (decrements in learning and memory). The enhancement of immunoregulatory processes, such as increasing anti-inflammatory cytokines...
Article
Aging is a major risk factor for developing postoperative cognitive dysfunction. Neuroinflammatory processes, which can play a causal role in the etiology of postoperative cognitive dysfunction, are potentiated or primed as a function of aging. Here we explored whether exposure to a microorganism with immunoregulatory and anti-inflammatory properti...
Poster
Full-text available
Glucocorticoids (GCs) have universally been considered anti-inflammatory. However, mounting evidence now demonstrates that GCs can exert paradoxical effects on innate immune function. In the context of stress exposure, GCs have been found to mediate stress-induced priming of neuroinflammatory responses to subsequent immune challenges. Recent eviden...
Article
Exposure to stressors induces anxiety- and depressive-like behaviors, which are mediated, in part, by neuroinflammatory processes. Recent findings demonstrate that treatment with the immunoregulatory and anti-inflammatory bacterium, Mycobacterium vaccae (M. vaccae), attenuates stress-induced exaggeration of peripheral inflammation and stress-induce...
Article
Mounting evidence indicates that cytokines secreted by innate immune cells in the brain play a central role in regulating neural circuits that subserve mood, cognition, and sickness responses. A major impediment to the study of neuroimmune signaling in healthy and disease states is the absence of tools for in vivo detection of cytokine release in t...
Article
Full-text available
The opioid inactive isomer (+)-naltrexone is one of the rare Toll-like receptor 4 (TLR4) antagonists with good blood-brain barrier (BBB) permeability, which is a lead with promising potential for treating neuropathic pain and drug addiction. (+)-Naltrexone targets the lipopolysaccharides (LPS) binding pocket of myeloid differentiation protein 2 (MD...
Article
Full-text available
Stress is a potent etiological factor in the onset of major depressive disorder and posttraumatic stress disorder (PTSD). Therefore, significant efforts have been made to identify factors that produce resilience to the outcomes of a later stressor, in hopes of preventing untoward clinical outcomes. The NMDA receptor antagonist ketamine has recently...
Article
Exposure to stressors can enhance neuroinflammatory responses, and both stress and neuroinflammation are predisposing factors in the development of psychiatric disorders. Females suffer disproportionately more from several psychiatric disorders, yet stress-induced changes in neuroinflammation have primarily been studied in males. Here we tested whe...
Article
Background: Opioids are effective postoperative analgesics. Disturbingly, we have previously reported that opioids such as morphine can worsen inflammatory pain and peripheral and central neuropathic pain. These deleterious effects are mediated by immune mediators that promote neuronal hyperexcitability in the spinal dorsal horn. Herein, we tested...
Article
Central neuropathic pain is a debilitating outcome of spinal cord injury (SCI) and current treatments to alleviate this pain condition are ineffective. A growing body of literature suggests that activating adenosine A2A receptors (A2ARs) decreases the production of proinflammatory cytokines and increases the production of anti-inflammatory cytokine...
Poster
Full-text available
The degree of behavioral control a subject (rat to human) can exert over an adverse life event is one of the most potent variables yet discovered that modulates the impact of that event. That is when a subject is provided with a controlling response the behavioral and neurochemical sequelae are blunted or eliminated. Prior work has established that...
Article
Exposure to stressors primes the neuroinflammatory and microglial proinflammatory response to subsequent immune challenges, suggesting that stress might attenuate immunoregulatory mechanisms in the CNS microenvironment. CD200:CD200R is a key immunoregulatory signaling dyad that constrains microglial activation, and disruption of CD200:CD200R signal...
Article
One of the fundamental mechanisms whereby the innate immune system coordinates inflammatory signal transduction is through Toll-like receptors (TLRs), which function to protect and defend the host organism by initiating inflammatory signaling cascades in response to tissue damage or injury. TLRs are positioned at the neuroimmune interface, and accu...
Article
Cocaine addiction is a chronic relapsing disorder characterized by persistent perturbations to an organism's homeostatic processes that result in maladaptive drug seeking. Although considerable attention has been directed at the consequences of neuronal changes following chronic cocaine taking, few studies have examined the role of microglia, the b...
Article
We have recently reported that a short course of morphine, starting 10 days after sciatic chronic constriction injury (CCI), prolonged the duration of mechanical allodynia for months after morphine ceased. Maintenance of this morphine-induced persistent sensitization was dependent on spinal NOD-like receptor protein 3 (NLRP3) inflammasomes-protein...
Article
Full-text available
MicroRNAs (miRNAs) are small noncoding RNAs that broadly affect cellular and physiological function in all multicellular organisms. Here, the role of miRNAs in neuroinflammation is considered. miRNAs are 21- to 23-oligonucleotide RNAs that regulate translation of specific RNAs by binding to complementary regulatory RNA sequences, thereby causing mR...
Article
More Americans are consuming diets higher in saturated fats and refined sugars than ever before, and based on increasing obesity rates, this is a growing trend among older adults as well. While high saturated fat diet (HFD) consumption has been shown to sensitize the inflammatory response to a subsequent immune challenge in young adult rats, the in...
Article
Spinal cord injury (SCI) causes chronic pain in 65% of individuals. Unfortunately, current pain management is inadequate for many SCI patients. Rodent models could help identify how SCI pain develops, explore new treatment strategies, and reveal whether acute post-SCI morphine worsens chronic pain. However, few studies explore or compare SCI-elicit...
Article
Full-text available
Early-life conditions can contribute to the propensity for developing neuropsychiatric disease, including substance abuse disorders. However, the long-lasting mechanisms that shape risk or resilience for drug addiction remain unclear. Previous work has shown that a neonatal handling procedure in rats (which promotes enriched maternal care) attenuat...
Article
Facial allodynia is a migraine symptom that is generally considered to represent a pivotal point in migraine progression. Treatment before development of facial allodynia tends to be more successful than treatment afterwards. As such, understanding the underlying mechanisms of facial allodynia may lead to a better understanding of the mechanisms un...
Article
Despite pain being a sensory experience, studies of spinal cord ventral root damage have demonstrated that motor neuron injury can induce neuropathic pain. Whether injury of cranial motor nerves can also produce nociceptive hypersensitivity has not been addressed. Herein, we demonstrate that chronic constriction injury (CCI) of the buccal branch of...
Article
Full-text available
Here, we present data demonstrating that a 1 d Morris water maze training protocol is effective at producing stable, longterm spatial memory in both young (3 mo old) and aged (24 mo old) F344xBN rats. Four trials in each of four sessions separated by a 2.5 h ISI produced robust selective search for the platform 1 and 4 d after training, in both age...
Article
Tissue injury can initiate bidirectional signaling between neurons, glia, and immune cells that creates and amplifies pain. While the ability for neurotransmitters, neuropeptides, and cytokines to initiate and maintain pain has been extensively studied, recent work has identified a key role for reactive oxygen and nitrogen species (ROS/RNS; nitroxi...
Article
Full-text available
Exposure to uncontrollable stress [inescapable tailshock (IS)] produces behavioral changes that do not occur if the stressor is controllable [escapable tailshock (ES)] an outcome that is mediated by greater IS-induced dorsal raphe nucleus (DRN) serotonin [5-hydroxytryptamine (5-HT)] activation. It has been proposed that this differential activation...
Article
Full-text available
Infectious and sterile inflammatory diseases are correlated with increased levels of high mobility group box 1 (HMGB1) in tissues and serum. Extracellular HMGB1 is known to activate Toll-like receptors (TLRs) 2 and 4 and RAGE (receptor for advanced glycation endproducts) in inflammatory conditions. Here, we find that TLR5 is also an HMGB1 receptor...
Article
Full-text available
In the central nervous system, bidirectional signaling between glial cells and neurons ('neuroimmune communication') facilitates the development of persistent pain. Spinal glia can contribute to heightened pain states by a prolonged release of neurokine signals that sensitize adjacent centrally projecting neurons. Although many persistent pain cond...
Article
Full-text available
The impact of the foods we eat on metabolism and cardiac physiology has been studied for decades, yet less is known about the effects of foods on the CNS, or the behavioral manifestations that may result from these effects. Previous studies have shown that long-term consumption of high-fat foods leading to diet-induced obesity sensitizes the inflam...
Article
Central neuropathic pain (CNP) is a pervasive, debilitating problem that impacts thousands of people living with central nervous system disorders, including spinal cord injury (SCI). Current therapies for treating this type of pain are ineffective and often have dose-limiting side effects. Although opioids are one of the most commonly used CNP trea...
Article
Unlabelled: Amplified neuroinflammatory responses following an immune challenge occur with normal aging and can elicit or exacerbate neuropathology. The mechanisms mediating this sensitized or "primed" immune response in the aged brain are not fully understood. The alarmin high mobility group box 1 (HMGB1) can be released under chronic pathologica...
Article
Exercise is known to exert a systemic anti-inflammatory influence, but whether its effects are sufficient to protect against subsequent neuropathic pain is underinvestigated. We report that 6 weeks of voluntary wheel running terminating before chronic constriction injury (CCI) prevented the full development of allodynia for the ;3-month duration of...