Karin N Westlund | University of Kentucky (original) (raw)

Papers by Karin N Westlund

Progress in clinical and biological research

1. Prog Clin Biol Res. 1982;79:115-30. Mapping monoaminergic and peptidergic pathways. Bowker RM,... more 1. Prog Clin Biol Res. 1982;79:115-30. Mapping monoaminergic and peptidergic pathways. Bowker RM, Westlund KN, Sullivan MC, Coulter JD. PMID: 6124002 [PubMed - indexed for MEDLINE]. Publication Types: Research Support, US Gov't, PHS; Review. MeSH Terms. ...

Journal of oral & facial pain and headache, 2015

To determine whether self-regulation can be studied successfully in a rodent model and whether pe... more To determine whether self-regulation can be studied successfully in a rodent model and whether persistent facial pain influences self-regulatory behavior. Thirty male Sprague-Dawley rats, divided into two groups, (1) chronic constriction injury of the infraorbital nerve (CCI-ION) and (2) naïve, were used in a two-part behavioral paradigm of self-regulation. This paradigm consisted of both a cued go/no-go task (part one) and a persistence trial (part two). All animals were acclimated and trained for a period of 4 weeks prior to the experimental manipulation and then tested for a total of 5 weeks following experimental manipulation. Results were analyzed with t tests, one-way analysis of variance, and two-way, repeated measures analysis of variance. CCI-ION surgery induced significant mechanical hypersensitivity of the ipsilateral whisker pad that began 3 weeks postsurgery and persisted through the duration of the experiment (P < .001). At weeks 4 and 5 post-experimental manipulati...

International journal of hepatology, 2012

Babesiosis, a common disease of animals, can infect humans via vector "tick bite", part... more Babesiosis, a common disease of animals, can infect humans via vector "tick bite", particularly in endemic areas. The recent reports of fatal cases in Hepatitis C and postliver transplant patients resulting from transfusion of contaminated blood should alert the medical profession regarding this emerging dilemma in endemic as well as nonendemic areas and the need for accurate blood screening for transfusion. Here, we illustrate different stages of the parasite lifecycle, progression of babesiosis in animal model, some aspects of pathologic outcomes, ongoing therapeutic modalities, and a feasible Acridine Orange fluorescent methodology for the diagnostic evaluation of blood samples.

Progress in brain research, 1996

During the past 5 years, our group has investigated the mechanisms of central sensitization of no... more During the past 5 years, our group has investigated the mechanisms of central sensitization of nociceptive pathways using 2 animal models: intradermal injection of capsaicin reviewed in Willis, 1994) and induction of acute arthritis Westlund, 1992, 1993a-d;; see review by . We have also explored the possibility of provoking sensitization more directly by administering drugs into the dorsal horn, either by iontophoresis or by microdialysis Dougherty et al., , 1995 Palecek et al., 1993a,b). Agents administered have included neurotransmitter agonists and antagonists, as well as drugs affecting second messenger systems. Central sensitization is characterized in our experiments by the following: (1) changes in the responses of primate spinothalamic tract (STT) neurons to stimulation of the skin, including increased responses to innocuous and marginally noxious stimuli and an enlarged receptive field; (2) behavioral responses to stimulation of the skin in rats indicative of allodynia and/or hyperalgesia; (3) morphological alterations in the dorsal horn in rats and monkeys; (4) and release of neurotransmitters into the dorsal horn, as determined by microdialysis and high performance liquid chromatography (HPLC) in rats and monkeys.

Journal of neurophysiology, 1996

1. Chronic arthritis was produced in rats by the injection of incomplete Freund's adjuvant in... more 1. Chronic arthritis was produced in rats by the injection of incomplete Freund's adjuvant into one knee joint. By 3-5 days later the rats had developed unilateral swelling of the injected knee and demonstrated bilateral hyperalgesia to radiant heat stimuli applied to the foot. 2. In the same rats anesthetized 3-5 days after the injection, dorsal root reflexes could be recorded bilaterally from the proximal ends of the cut medial articular nerves (MANs) of the knee joint. 3. The dorsal root reflexes consisted of large, medium-sized, and small action potentials evoked in response to phasic mechanical stimulation of the lateral aspect of the knee. The activity was greater in the MAN ipsilateral to the injection than in the contralateral MAN. 4. Local application of capsaicin on the side ipsilateral or contralateral to the arthritis dramatically reduced the dorsal root reflexes recorded from the contralateral MAN, indicating that these dorsal root reflexes depended on activity in f...

The Journal of physiology, Jan 15, 1995

1. In rats anaesthetized with pentobarbitone sodium, a unilateral acute arthritis was produced by... more 1. In rats anaesthetized with pentobarbitone sodium, a unilateral acute arthritis was produced by the injection of kaolin and carrageenan into one knee-joint cavity. Four hours after injection, the medial articular nerve (MAN) was sectioned distally and recordings obtained from the proximal stump of the nerve. 2. Centrifugally conducted action potentials were recorded from the cut MAN following the development of arthritis. Acute dorsal rhizotomy, but not sympathectomy, prevented the action potentials, and so it is concluded that the action potentials represent dorsal root reflexes. 3. Central administration of either the GABAA receptor antagonist, bicuculline, or the non-NMDA receptor antagonist, CNQX, also prevented dorsal root reflexes in the MAN. 4. Neither the GABAB receptor antagonist, CGP35348, nor the NMDA receptor antagonist, AP7, altered the dorsal root reflexes in the MAN. 5. It is concluded that arthritis causes excess primary afferent depolarization in the dorsal horn o...

Journal of neurophysiology, 1995

1. Injection of kaolin and carrageenan into the knee joint of cats or monkeys resulted in an acut... more 1. Injection of kaolin and carrageenan into the knee joint of cats or monkeys resulted in an acute inflammation. Four hours after injection of the knee joint, efferent activity could be evoked in articular afferent fibers and in dorsal root filaments. We interpret this efferent activity to be dorsal root reflexes (DRRs). Under our experimental conditions, the DRRs were generally synchronized compound action potentials, although in some cases single-unit activity was also observed. 2. DRRs were not produced in animals with uninflamed knee joints and normal body temperatures. 3. Recordings from two different sites on cut dorsal root filaments ipsilateral to the inflamed knee joint allowed the determination of the conduction velocities of groups of afferent fibers carrying DRRs. The DRRs occurred in A beta-, A delta-, and C fibers. However, in these experiments the peripheral destination of the afferent fibers was unknown. 4. To prove that DRRs occurred in joint afferents, recordings w...

Neuroscience, 2015

Reduced catechol-O-methyltransferase (COMT) activity resulting from genetic variation or pharmaco... more Reduced catechol-O-methyltransferase (COMT) activity resulting from genetic variation or pharmacological depletion results in enhanced pain perception in humans and nociceptive behaviors in animals. Using phasic mechanical and thermal reflex tests (e.g. von Frey, Hargreaves), recent studies show that acute COMT-dependent pain in rats is mediated by b-adrenergic receptors (bARs). In order to more closely mimic the characteristics of human chronic pain conditions associated with prolonged reductions in COMT, the present study sought to determine volitional pain-related and anxiety-like behavioral responses following sustained as well as acute COMT inhibition using an operant 10-45°C thermal place preference task and a light/dark preference test. In addition, we sought to evaluate the effects of sustained COMT inhibition on generalized body pain by measuring tactile sensory thresholds of the abdominal region. Results demonstrated that acute and sustained administration of the COMT inhibitor OR486 increased pain behavior in response to thermal heat. Further, sustained administration of OR486 increased anxiety behavior in response to bright light, as well as abdominal mechanosensation. Finally, all pain-related behaviors were blocked by the non-selective bAR antagonist propranolol. Collectively, these findings provide the first evidence that stimulation of bARs following acute or chronic COMT inhibition drives cognitive-affective behaviors associated with heightened pain that affects multiple body sites.

Anesthesiology, 2003

Most animal models of pancreatitis are short-lived or very invasive. A noninvasive animal model o... more Most animal models of pancreatitis are short-lived or very invasive. A noninvasive animal model of pancreatitis developed in highly inbred rats by Merkord with symptoms persisting for 3 weeks was adopted in the current study to test its validity as a model of visceral pain in commercially available rats. The persistent pancreatitis model was established by tail vein injection of dibutyltin dichloride. Animals were given 10% alcohol in their drinking water to enhance the pancreatitis attack. Blood serum pancreatic enzymes and nociceptive state were monitored for 3 weeks after dibutyltin dichloride or vehicle. Behavioral testing included reflexive withdrawal to mechanical and thermal stimulation of the abdominal area. The effect of morphine on nociceptive behaviors was tested. Histologic analysis of the pancreas and immunohistochemical analysis of substance P and calcitonin gene-related peptide in the spinal cord are included in the study. Compared with naïve and vehicle-only injected control groups, rats receiving dibutyltin dichloride demonstrated an increase in withdrawal events after von Frey stimulation and decreased withdrawal latency after thermal stimulation, signaling a sensitized nociceptive state through 7 days. These pain-related measures were abrogated by morphine. Blood serum concentrations of amylase and lipase as well as tissue inflammatory changes and substance P were also significantly elevated during this same time period. These results indicate that animals with the dibutyltin dichloride-induced experimental pancreatitis expressed serum, histologic, and behavioral characteristics similar in duration to those present during acute attacks experienced by patients with chronic pancreatitis. These findings and responsivity to morphine suggest the utility of this model developed in a commercially available strain of rats for study of persistent visceral pain.

Brain Research, 2001

The present study demonstrates sites of expression for Fos protein in the brainstem and lumbosacr... more The present study demonstrates sites of expression for Fos protein in the brainstem and lumbosacral spinal cord of rats subjected to mustard oil irritation of the colon. The protective effect of baclofen, a selective GABAB receptor agonist, on the induced Fos protein increases was determined. Mustard oil injected into the lumen of the colon produces an acute site-specific inflammation. Immunocytochemical

Brain Research, 2002

Glutamate is a major excitatory neurotransmitter in the mammalian CNS. After its release, specifi... more Glutamate is a major excitatory neurotransmitter in the mammalian CNS. After its release, specific transporter proteins rapidly remove extracellular glutamate from the synaptic cleft. The clearance of excess extracellular glutamate prevents accumulation under normal conditions; however, CNS injury elevates extracellular glutamate concentrations to neurotoxic levels. The purpose of this study was to examine changes in expression and in spatial localization

NeuroReport, 1997

The role of a newly identified component of the postsynaptic dorsal column (PSDC) system in visce... more The role of a newly identified component of the postsynaptic dorsal column (PSDC) system in viscerosensory processing has been recently described. The purpose of this study was to examine the effect of colon inflammation on the responses of single PSDC cells, located in the vicinity of the central canal at L6-S1 spinal segments, to graded colorectal distension (CRD) and to cutaneous stimulation. Experiments were conducted on seven male Sprague-Dawley rats anesthetized with pentobarbital. Recordings were made from seven PSDC cells located around the central canal at L6-S1 in response to CRD and cutaneous stimulation before and after colon inflammation. Inflammation of the colon with mustard oil (MO) induced an increase in the background activity of these cells. Colon inflammation also potentiated the responses of the PSDC cells to graded CRD but not to cutaneous stimulation. This is consistent with previously observed effects of colon inflammation on the responses of viscerosensitive cells in the ventral posterolateral (VPL) nucleus of the thalamus and in the nucleus gracilis (NG). These observations support a role of the PSDC system in viscerosensory processing and primary visceral hyperalgesia.

NeuroReport, 1994

Efferent activity was recorded in knee joint afferents in response to mechanical stimulation of t... more Efferent activity was recorded in knee joint afferents in response to mechanical stimulation of the hindlimb following induction of acute arthritis. The activity was abolished by application of lidocaine or crushing the nerve proximally and by dorsal rhizotomy but not by sympathectomy. It was concluded that this activity represents dorsal root reflexes in response to natural stimulation of the hindlimb. We propose that increased activity of articular afferents and of dorsal horn neurons during arthritis results in the pathological activation of the central terminals of primary afferents by enhancing primary afferent depolarization. Dorsal root reflexes could then release substances in the knee joint and thus contribute to the acute inflammatory response.

Neuroimage, 2009

Abdominal pain is a major reason patients seek medical attention yet relatively little is known a... more Abdominal pain is a major reason patients seek medical attention yet relatively little is known about neuronal pathways relaying visceral pain. We have previously characterized pathways transmitting information to the brain about visceral pain. Visceral pain arises from second order neurons in lamina X surrounding the spinal cord central canal. Some of the brain regions of interest receiving axonal terminations directly from lamina X were examined in the present study using enhanced functional magnetic resonance imaging (fMRI) before and one week after induction of a rat pancreatitis model with persistent inflammation and behavioral signs of increased nociception. Analysis of imaging data demonstrates an increase in MRI signal for all the regions of interest selected including the rostral ventromedial medulla, dorsal raphe, periaqueductal grey, medial thalamus, and central amygdala as predicted by the anatomical data, as well as increases in the lateral thalamus, cingulate/retrosplenial and parietal cortex. Occipital cortex was not activated above threshold in any condition and served as a negative control. Morphine attenuated the MRI signal, and the morphine effect was antagonized by naloxone in lower brainstem sites. These data confirm activation of these specific regions of interest known as integration sites for nociceptive information important in behavioral, affective, emotional and autonomic responses to ongoing noxious visceral activation.

Progress in pain research and management, 1994

Pain, 1996

The present report provides evidence that axons in the medial part of the posterior column at T10... more The present report provides evidence that axons in the medial part of the posterior column at T10 convey ascending nociceptive signals from pelvic visceral organs. This evidence was obtained from human surgical case studies and histological verification of the lesion in one of these cases, along with neuroanatomical and neurophysiological findings in animal experiments. A restricted lesion in this area can virtually eliminate pelvic pain due to cancer. The results remain excellent even in cases in which somatic structures of the pelvic body wall are involved. Following this procedure, neurological testing reveals no additional neurological deficit. There is no analgesia to pinprick stimuli applied to the body surface, despite the relief of the visceral pain. Since it is reasonable to attribute the favorable results of limited midline myelotomies to the interruption of axons of visceral nociceptive projection neurons in the posterior column, we have performed experiments in rats to test this hypothesis. The results in rats indicate that the dorsal column does indeed include a nociceptive component that signals pelvic visceral pain. The pathway includes neurons of the postsynaptic dorsal column pathway at the L6-S1 segmental level, axons of these neurons in the fasciculus gracilis, and neurons of the nucleus gracilis and the ventral posterolateral nucleus of the thalamus.

Pflugers Archiv-european Journal of Physiology, 1998

The expression of isoform-specific dihydropyridine receptor Ca2+ channel (DHPR) α1-subunit genes ... more The expression of isoform-specific dihydropyridine receptor Ca2+ channel (DHPR) α1-subunit genes in rat diaphragm, soleus and extensor digitorum longus muscles was investigated using RNase protection assays. As expected, mRNA expression levels for the DHPR skeletal muscle isoform were highest in extensor digitorum longus. Unexpectedly, both diaphragm and soleus expressed mRNA for the cardiac isoform at a significant level. Moreover, immunohistochemical

Translational Research, 2012

Many aspects of tissue damage following acute or chronic inflammatory reactions can be directly a... more Many aspects of tissue damage following acute or chronic inflammatory reactions can be directly attributed to the concomitant biosynthesis and release of inducible early pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Conversely, systemic inflammation is impacted by consequences of tissue damage. Dysregulated TNFα contributes to numerous pathophysiological conditions including inflammatory bowel disease (IBD) and arthritis. Inflammatory stimuli trigger proteolytic cleavage and shedding of extracellular domains of TNFα receptors giving rise to two soluble fragments (p55 sTNFR1 and p75 sTNFR2) that block further binding, activity and synthesis of TNFα. We hypothesized that absence of sTNFR inhibitory feedback control would result in accumulated high levels of TNFα and other inflammatory factors promoting the cardinal signs of chronic inflammation and pain.

Pharmacology Biochemistry and Behavior, 2004

The aim of this study was to determine the influence of a glutamate receptor antagonist or a prot... more The aim of this study was to determine the influence of a glutamate receptor antagonist or a protein kinase C (PKC) inhibitor on the central visceral nociceptive amplification process present in an experimental pancreatitis model. The acute pancreatitis model was produced by combining intraductal infusion of an irritative bile salt, glycodeoxycholic acid (GDOC), with intraperitoneal injection of a CCK analogue, caerulein, in male Sprague -Dawley rats. Exploratory activities were measured with an automated photobeam activity system and compared among different treatment groups. To confirm the inflammation, the pancreas was weighed and compared histologically with those taken from naive rats.

Pain, 2001

Peripheral in¯ammation induced with a knee joint injection of a mixture of kaolin/carrageenan (k/... more Peripheral in¯ammation induced with a knee joint injection of a mixture of kaolin/carrageenan (k/c) produces primary and secondary hyperalgesia. In¯ammatory pain is thought to involve a variety of transmitters released from nerve terminals, including amino acids, substance P (SP) and calcitonin gene-related peptide (CGRP). In the present study, mice de®cient in the calcitonin/aCGRP gene (CGRP(2/2)) displayed normal responses to noxious stimuli. However, the CGRP knockout mice failed to demonstrate development of secondary hyperalgesia after induction of knee joint in¯ammation in two tests that assess central sensitization, through testing at sites remote from the primary insult. Nociceptive behavioral responses were assessed using the hot-plate test and paw withdrawal latency (PWL) to radiant heat applied to the hindpaw. The CGRP(2/2) mice showed no signs of secondary hyperalgesia after development of knee joint in¯ammation, while the expected signi®cant decrease in the PWL was observed in the CGRP(1/1) mice as control. The CGRP(2/2) mice also had a prolonged rather than a shortened response latency in the hot-plate test 4 h after knee joint injection of k/c. Immunohistological study showed that CGRP-like immunoreactivity (CGRP-LI) was absent in the spinal cord and dorsal root ganglia taken from the CGRP(2/2) mice. These results indicate that endogenous CGRP plays an important role in the plastic neurogenic changes occurring in response to peripheral in¯ammatory events including the development of nociceptive behaviors.