Publications by authors named "Luc Jasmin"

37 Publications

Agomelatine effects on fat-enriched diet induced neuroinflammation and depression-like behavior in rats.

Biomed Pharmacother 2021 Mar 1;135:111246. Epub 2021 Feb 1.

Laboratory of Biotechnology, National Higher School of Biotechnology, Ville universitaire Ali Mendjeli, BP E66 25100, Constantine, Algeria. Electronic address:

Growing evidence suggests that a high fat diet (HFD) induces oxidative stress on the central nervous system (CNS), which predisposes to mood disorders and neuroinflammation. In this study we postulated that in addition to improving mood, antidepressant therapy would reverse inflammatory changes in the brain of rats exposed to a HFD. To test our hypothesis, we measured the effect of the antidepressant agomelatine (AGO) on anxiety- and depressive-like behaviors, as well as on CNS markers of inflammation in rats rendered obese. Agomelatine is an agonist of the melatonin receptors MT1 and MT2 and an antagonist of the serotonin receptors 5HT2B and 5HT2C. A subset of rats was also treated with lipopolysaccharides (LPS) to determine how additional neuroinflammation alters behavior and affects the response to the antidepressant. Specifically, rats were subjected to a 14-week HFD, during which time behavior was evaluated twice, first at the 10th week prior to LPS and/or agomelatine, and then at the 14th week after a bi-weekly exposure to LPS (250 μg/kg) and daily treatment with agomelatine (40 mg/kg). Immediately after the second behavioral testing we measured the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β), markers of oxidative stress thiobarbituric acid reactive substances (TABRS), catalase (CAT) and glutathione peroxidase (GPx), the growth factor BDNF, as well as the apoptosis marker caspase-3. Our results show that a HFD induced an anxiety-like behavior in the open field test (OFT) at the 10th week, followed by a depressive-like behavior in the forced swim test (FST) at the 14th week. In the prefrontal and hippocampal cortices of rats exposed to a HFD we noted an overproduction of TNF-α, IL-6, IL-1β, and TABRS, together with an increase in caspase-3 activity. We also observed a decrease in BDNF, as well as reduced CAT and GPx activity in the same brain areas. Treatment with agomelatine reversed the signs of anxiety and depression, and decreased the cytokines (TNF-α, IL-6 and IL-1β), TABRS, as well as caspase-3 activity. Agomelatine also restored BDNF levels and the activity of antioxidant enzymes CAT and GPx. Our findings suggest that the anxiolytic/antidepressant effect of agomelatine in obese rats could result from a reversal of the inflammatory and oxidative stress brought about by their diet.
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http://dx.doi.org/10.1016/j.biopha.2021.111246DOI Listing
March 2021

Pain Genes?

Authors:
Luc Jasmin

J Invest Surg 2020 02 6;33(2):181. Epub 2018 Jun 6.

Department of Oral and Maxillofacial Surgery, UCSF, San Francisco, CA, USA.

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http://dx.doi.org/10.1080/08941939.2018.1474981DOI Listing
February 2020

Dual effects of brain sparing opioid in newborn rats: Analgesia and hyperalgesia.

Neurobiol Pain 2018 Jan-Jul;3:1-7. Epub 2018 Jan 10.

Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA, United States.

Effective pain management in neonates without the unwanted central nervous system (CNS) side effects remains an unmet need. To circumvent these central effects we tested the peripherally acting (brain sparing) opioid agonist loperamide in neonate rats. Our results show that: 1) loperamide (1 mg/kg, s.c.) does not affect the thermal withdrawal latency in the normal hind paw while producing antinociception in all pups with an inflamed hind paw. 2) A dose of loperamide 5 times higher resulted in only 6.9 ng/mL of loperamide in the cerebrospinal fluid (CSF), confirming that loperamide minimally crosses the blood-brain barrier (BBB). 3) Unexpectedly, sustained administration of loperamide for 5 days resulted in a hyperalgesic behavior, as well as increased excitability (sensitization) of dorsal root ganglia (DRGs) and spinal nociceptive neurons. This indicates that opioid induced hyperalgesia (OIH) can be induced through the peripheral nervous system. Unless prevented, OIH could in itself be a limiting factor in the use of brain sparing opioids in the neonate.
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http://dx.doi.org/10.1016/j.ynpai.2018.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550121PMC
January 2018

The antidepressant effect of melatonin and fluoxetine in diabetic rats is associated with a reduction of the oxidative stress in the prefrontal and hippocampal cortices.

Brain Res Bull 2017 Sep 23;134:142-150. Epub 2017 Jul 23.

National Higher School of Biotechnology, Ville universitaire Ali Mendjeli, BP E66 25100 Constantine, Algeria. Electronic address:

In the past few years possible mechanisms that link diabetes and depression have been found. One of these mechanisms is the increase in lipid peroxidation and decrease in antioxidant activity in the hippocampal and prefrontal cortices, which are brain areas involved in mood. The goal of the present study was to evaluate the effect of an antidepressant and of an antioxidant on behavior and oxidative activity in brains of diabetic rats. Rats rendered diabetic after a treatment with streptozotocin (STZ) (60mg/kg) were treated with fluoxetine (15mg/kg), melatonin (10mg/kg), or vehicle for 4 weeks. All animals were tested for signs of depression and anxiety using the elevated plus maze (EPM), open field test (OFT) and the forced swim test (FST). Four groups were compared: (1) normoglycemic, (2) hyperglycemic vehicle treated, and hyperglycemic (3) fluoxetine or (4) melatonin treated rats. On the last day of the study, blood samples were obtained to determine the levels of hemoglobin A1c (HbA1c). Also, brain samples were collected to measure the oxidative stress in the hippocampal and prefrontal cortices using the thiobarbituric acid reactive substances (TBARS) assay. The activity of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx), and glutathione S-transferase (GST) were also measured on the brain samples. The results show that both fluoxetine and melatonin decrease the signs of depression and anxiety in all tests. Concomitantly, the levels of HbA1c were reduced in drug treated rats, and to a greater degree in the fluoxetine group. In the cerebral cortex of diabetic rats, TBARS was increased, while the activity of CAT, GPx and GST were decreased. Fluoxetine and melatonin treatments decreased TBARS in both cortices. In the prefrontal cortex, fluoxetine and melatonin restored the activity of CAT, while only melatonin improved the activity of GPx and GST. In the hippocampus, the activity of GPx alone was restored by melatonin, while fluoxetine had no effect. These results suggest that antidepressants and antioxidants can counter the mood and oxidative disorders associated with diabetes. While these effects could result from a decreased production of reactive oxygen species (ROS) remains to be established.
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http://dx.doi.org/10.1016/j.brainresbull.2017.07.013DOI Listing
September 2017

Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia.

J Pain 2017 02 12;18(2):212-221. Epub 2016 Nov 12.

Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, California. Electronic address:

It is not uncommon for patients chronically treated with opioids to exhibit opioid-induced hyperalgesia, and this has been widely reported clinically and experimentally. The molecular substrate for this hyperalgesia is multifaceted, and associated with a complex neural reorganization even in the periphery. For instance, we have recently shown that chronic morphine-induced heat hyperalgesia is associated with an increased expression of GluN2B containing N-methyl-D-aspartate receptors, as well as of the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1, in small-diameter primary sensory neurons only. Cold allodynia is also a common complaint of patients chronically treated with opioids, yet its molecular mechanisms remain to be understood. Here we present evidence that the cold sensor TRPM8 channel is involved in opioid-induced hyperalgesia. After 7 days of morphine administration, we observed an upregulation of TRPM8 channels using patch clamp recording on sensory neurons and Western blot analysis on dorsal root ganglia. The selective TRPM8 antagonist RQ-00203078 blocked cold hyperalgesia in morphine-treated rats. Also, TRPM8 knockout mice failed to develop cold hyperalgesia after chronic administration of morphine. Our results show that chronic morphine upregulates TRPM8 channels, which is in contrast with the previous finding that acute morphine triggers TRPM8 internalization.

Perspective: Patients receiving chronic opioid are sensitive to cold. We show in mice and rats that sustained morphine administration induces cold hyperalgesia and an upregulation of TRPM8. Knockout or selectively blocking TRPM8 reduces morphine-induced cold hyperalgesia suggesting TRPM8 is regulated by opioids.
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http://dx.doi.org/10.1016/j.jpain.2016.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291755PMC
February 2017

Patch Clamp Recordings on Intact Dorsal Root Ganglia from Adult Rats.

J Vis Exp 2016 09 29(115). Epub 2016 Sep 29.

Department of Oral and Maxillofacial Surgery, University of California, San Francisco;

Patch clamp studies from dorsal root ganglia (DRGs) neurons have increased our understanding of the peripheral nervous system. Currently, the majority of recordings are conducted on dissociated DRG neurons, which is a standard preparation for most laboratories. Neuronal properties, however, can be altered by axonal injury resulting from enzyme digestion used in acquiring dissociated neurons. Further, dissociated neuron preparations cannot fully represent the microenvironment of the DRG since loss of contact with satellite glial cells that surround the primary sensory neurons is an unavoidable consequence of this method. To overcome the limitations in using conventional dissociated DRG neurons for patch clamp recordings, in this report we describe a method to prepare intact DRGs and conduct patch clamp recordings on individual primary sensory neurons ex vivo. This approach permits the fast and straightforward preparation of intact DRGs, mimicking in vivo conditions by keeping DRG neurons associated with their surrounding satellite glial cells and basement membrane. Furthermore, the method avoids axonal injury from manipulation and enzyme digestion such as when dissociating DRGs. This ex vivo preparation can additionally be used to study the interaction between primary sensory neurons and satellite glial cells.
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http://dx.doi.org/10.3791/54287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5092077PMC
September 2016

GluN2B N-methyl-D-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats: implication for opiate-induced hyperalgesia.

Pain 2016 Jan;157(1):147-158

Departments of Oral and Maxillofacial Surgery and Obstetric and Gynecology and the Osher Center for Integrative Medicine, University of California San Francisco, San Francisco, CA, USA.

The contribution of the peripheral nervous system to opiate-induced hyperalgesia (OIH) is not well understood. In this study, we determined the changes in excitability of primary sensory neurons after sustained morphine administration for 7 days. Changes in the expression of glutamate receptors and glutamate transporters after morphine administration were ascertained in dorsal root ganglions. Patch clamp recordings from intact dorsal root ganglions (ex vivo preparation) of morphine-treated rats showed increased excitability of small diameter (≤30 μm) neurons with respect to rheobase and membrane threshold, whereas the excitability of large diameter (>30 μm) neurons remained unchanged. Small diameter neurons also displayed increased responses to glutamate, which were mediated mainly by GluN2B containing N-methyl-D-aspartate (NMDA) receptors, and to a lesser degree by the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1. Coadministration in vivo of the GluN2B selective antagonist Ro 25-6981 with morphine for 7 days prevented the appearance of OIH and increased morphine-induced analgesia. Administration of morphine for 7 days led to an increased expression of GluN2B and excitatory amino acid transporter 3/excitatory amino acid carrier 1, but not of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate, kainate, or group I metabotropic glutamate receptors, or of the vesicular glutamate transporter 2. These results suggest that peripheral glutamatergic neurotransmission contributes to OIH and that GluN2B subunit of NMDA receptors in the periphery may be a target for therapy.
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http://dx.doi.org/10.1097/j.pain.0000000000000342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957526PMC
January 2016

Increased response to glutamate in small diameter dorsal root ganglion neurons after sciatic nerve injury.

PLoS One 2014 18;9(4):e95491. Epub 2014 Apr 18.

Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, California, United States of America; Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America.

Glutamate in the peripheral nervous system is involved in neuropathic pain, yet we know little how nerve injury alters responses to this neurotransmitter in primary sensory neurons. We recorded neuronal responses from the ex-vivo preparations of the dorsal root ganglia (DRG) one week following a chronic constriction injury (CCI) of the sciatic nerve in adult rats. We found that small diameter DRG neurons (<30 µm) exhibited increased excitability that was associated with decreased membrane threshold and rheobase, whereas responses in large diameter neurons (>30 µm) were unaffected. Puff application of either glutamate, or the selective ionotropic glutamate receptor agonists alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid (KA), or the group I metabotropic receptor (mGluR) agonist (S)-3,5-dihydroxyphenylglycine (DHPG), induced larger inward currents in CCI DRGs compared to those from uninjured rats. N-methyl-D-aspartate (NMDA)-induced currents were unchanged. In addition to larger inward currents following CCI, a greater number of neurons responded to glutamate, AMPA, NMDA, and DHPG, but not to KA. Western blot analysis of the DRGs revealed that CCI resulted in a 35% increase in GluA1 and a 60% decrease in GluA2, the AMPA receptor subunits, compared to uninjured controls. mGluR1 receptor expression increased by 60% in the membrane fraction, whereas mGluR5 receptor subunit expression remained unchanged after CCI. These results show that following nerve injury, small diameter DRG neurons, many of which are nociceptive, have increased excitability and an increased response to glutamate that is associated with changes in receptor expression at the neuronal membrane. Our findings provide further evidence that glutamatergic transmission in the periphery plays a role in nociception.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095491PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991716PMC
May 2015

Satellite glial cell proliferation in the trigeminal ganglia after chronic constriction injury of the infraorbital nerve.

Glia 2013 Dec 3;61(12):2000-8. Epub 2013 Oct 3.

University of California San Francisco, Center for Integrative Neuroscience, BOX 0444, 675 Nelson Rising Lane, San Francisco, California.

We have examined satellite glial cell (SGC) proliferation in trigeminal ganglia following chronic constriction injury of the infraorbital nerve. Using BrdU labeling combined with immunohistochemistry for SGC specific proteins we positively confirmed proliferating cells to be SGCs. Proliferation peaks at approximately 4 days after injury and dividing SGCs are preferentially located around neurons that are immunopositive for ATF-3, a marker of nerve injury. After nerve injury there is an increase GFAP expression in SGCs associated with both ATF-3 immunopositive and immunonegative neurons throughout the ganglia. SGCs also express the non-glial proteins, CD45 and CD163, which label resident macrophages and circulating leukocytes, respectively. In addition to SGCs, we found some Schwann cells, endothelial cells, resident macrophages, and circulating leukocytes were BrdU immunopositive.
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http://dx.doi.org/10.1002/glia.22571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040138PMC
December 2013

Evidence for glutamate as a neuroglial transmitter within sensory ganglia.

PLoS One 2013 2;8(7):e68312. Epub 2013 Jul 2.

Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America.

This study examines key elements of glutamatergic transmission within sensory ganglia of the rat. We show that the soma of primary sensory neurons release glutamate when depolarized. Using acute dissociated mixed neuronal/glia cultures of dorsal root ganglia (DRG) or trigeminal ganglia and a colorimetric assay, we show that when glutamate uptake by satellite glial cells (SGCs) is inhibited, KCl stimulation leads to simultaneous increase of glutamate in the culture medium. With calcium imaging we see that the soma of primary sensory neurons and SGCs respond to AMPA, NMDA, kainate and mGluR agonists, and selective antagonists block this response. Using whole cell patch-clamp technique, inward currents were recorded from small diameter (<30 µm) DRG neurons from intact DRGs (ex-vivo whole ganglion preparation) in response to local application of the above glutamate receptor agonists. Following a chronic constriction injury (CCI) of either the inferior orbital nerve or the sciatic nerve, glutamate expression increases in the trigeminal ganglia and DRG respectively. This increase occurs in neurons of all diameters and is present in the somata of neurons with injured axons as well as in somata of neighboring uninjured neurons. These data provides additional evidence that glutamate can be released within the sensory ganglion, and that the somata of primary sensory neurons as well as SGCs express functional glutamate receptors at their surface. These findings, together with our previous gene knockdown data, suggest that glutamatergic transmission within the ganglion could impact nociceptive threshold.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0068312PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699553PMC
February 2014

Orofacial pain models and behavior assessment.

Methods Mol Biol 2012 ;851:159-70

Department of Anatomy, University of California San Francisco, San Francisco, CA, USA.

Orofacial pain remains an understudied area in pain research given that most attention has been focused on the spinal system. In this chapter, animal models of neuropathic and inflammatory orofacial pain are presented. Four different types of pain behavior tests are then described for assessing evoked and spontaneous pain behavior in addition to conditional reward behavior. The use of a combination of different pain models and behavior assessments is needed to aid in understanding the mechanisms contributing to orofacial pain in humans for developing effective therapy.
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http://dx.doi.org/10.1007/978-1-61779-561-9_11DOI Listing
July 2012

Temporomandibular joint inflammation activates glial and immune cells in both the trigeminal ganglia and in the spinal trigeminal nucleus.

Mol Pain 2010 Dec 10;6:89. Epub 2010 Dec 10.

Department of Pharmacological Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.

Background: Glial cells have been shown to directly participate to the genesis and maintenance of chronic pain in both the sensory ganglia and the central nervous system (CNS). Indeed, glial cell activation has been reported in both the dorsal root ganglia and the spinal cord following injury or inflammation of the sciatic nerve, but no data are currently available in animal models of trigeminal sensitization. Therefore, in the present study, we evaluated glial cell activation in the trigeminal-spinal system following injection of the Complete Freund's Adjuvant (CFA) into the temporomandibular joint, which generates inflammatory pain and trigeminal hypersensitivity.

Results: CFA-injected animals showed ipsilateral mechanical allodynia and temporomandibular joint edema, accompanied in the trigeminal ganglion by a strong increase in the number of GFAP-positive satellite glial cells encircling neurons and by the activation of resident macrophages. Seventy-two hours after CFA injection, activated microglial cells were observed in the ipsilateral trigeminal subnucleus caudalis and in the cervical dorsal horn, with a significant up-regulation of Iba1 immunoreactivity, but no signs of reactive astrogliosis were detected in the same areas. Since the purinergic system has been implicated in the activation of microglial cells during neuropathic pain, we have also evaluated the expression of the microglial-specific P2Y12 receptor subtype. No upregulation of this receptor was detected following induction of TMJ inflammation, suggesting that any possible role of P2Y12 in this paradigm of inflammatory pain does not involve changes in receptor expression.

Conclusions: Our data indicate that specific glial cell populations become activated in both the trigeminal ganglia and the CNS following induction of temporomandibular joint inflammation, and suggest that they might represent innovative targets for controlling pain during trigeminal nerve sensitization.
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http://dx.doi.org/10.1186/1744-8069-6-89DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017032PMC
December 2010

Close encounters of the third kind: evidence for contact with TNF-alpha.

Pain 2010 Nov 23;151(2):241-242. Epub 2010 Aug 23.

Department of Anatomy, UCSF, 513 Parnassus, San Francisco, CA 94143-0452, USA.

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http://dx.doi.org/10.1016/j.pain.2010.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955849PMC
November 2010

Can satellite glial cells be therapeutic targets for pain control?

Neuron Glia Biol 2010 Feb 22;6(1):63-71. Epub 2010 Jun 22.

Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.

Satellite glial cells (SGCs) undergo phenotypic changes and divide the following injury into a peripheral nerve. Nerve injury, also elicits an immune response and several antigen-presenting cells are found in close proximity to SGCs. Silencing SCG-specific molecules involved in intercellular transport (Connexin 43) or glutamate recycling (glutamine synthase) can dramatically alter nociceptive responses of normal and nerve-injured rats. Transducing SGCs with glutamic acid decarboxylase can produce analgesia in models of trigeminal pain. Taken together these data suggest that SGCs may play a role in the genesis or maintenance of pain and open a range of new possibilities for curing neuropathic pain.
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http://dx.doi.org/10.1017/S1740925X10000098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139431PMC
February 2010

Gliopathic pain: when satellite glial cells go bad.

Neuroscientist 2009 Oct;15(5):450-63

Department of Anatomy, University of California, San Francisco, California 95143-0452, USA.

Neurons in sensory ganglia are surrounded by satellite glial cells (SGCs) that perform similar functions to the glia found in the CNS. When primary sensory neurons are injured, the surrounding SGCs undergo characteristic changes. There is good evidence that the SGCs are not just bystanders to the injury but play an active role in the initiation and maintenance of neuronal changes that underlie neuropathic pain. In this article the authors review the literature on the relationship between SGCs and nociception and present evidence that changes in SGC potassium ion buffering capacity and glutamate recycling can lead to neuropathic pain-like behavior in animal models. The role that SGCs play in the immune responses to injury is also considered. We propose the term gliopathic pain to describe those conditions in which central or peripheral glia are thought to be the principal generators of principal pain generators.
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http://dx.doi.org/10.1177/1073858409336094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852320PMC
October 2009

Adenovector GAD65 gene delivery into the rat trigeminal ganglion produces orofacial analgesia.

Mol Pain 2009 Aug 5;5:42. Epub 2009 Aug 5.

Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA.

Background: Our goal is to use gene therapy to alleviate pain by targeting glial cells. In an animal model of facial pain we tested the effect of transfecting the glutamic acid decarboxylase (GAD) gene into satellite glial cells (SGCs) of the trigeminal ganglion by using a serotype 5 adenovector with high tropisms for glial cells. We postulated that GABA produced from the expression of GAD would reduce pain behavior by acting on GABA receptors on neurons within the ganglion.

Results: Injection of adenoviral vectors (AdGAD65) directly into the trigeminal ganglion leads to sustained expression of the GAD65 isoform over the 4 weeks observation period. Immunohistochemical analysis showed that adenovirus-mediated GAD65 expression and GABA synthesis were mainly in SGCs. GABAA and GABAB receptors were both seen in sensory neurons, yet only GABAA receptors decorated the neuronal surface. GABA receptors were not found on SGCs. Six days after injection of AdGAD65 into the trigeminal ganglion, there was a statistically significant decrease of pain behavior in the orofacial formalin test, a model of inflammatory pain. Rats injected with control virus (AdGFP or AdLacZ) had no reduction in their pain behavior. AdGAD65-dependent analgesia was blocked by bicuculline, a selective GABAA receptor antagonist, but not by CGP46381, a selective GABAB receptor antagonist.

Conclusion: Transfection of glial cells in the trigeminal ganglion with the GAD gene blocks pain behavior by acting on GABAA receptors on neuronal perikarya.
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http://dx.doi.org/10.1186/1744-8069-5-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734545PMC
August 2009

Pain free and awake to enjoy it!

Pain 2009 Feb 6;141(3):187-188. Epub 2009 Jan 6.

Los Angeles Neurosurgical Institute and Gene Therapeutics Research Institute at Cedars Sinai Medical Center, 8631 West Third St., Suite 800E, Los Angeles, CA 90048, USA Department of Anatomy, University of California, San Francisco, USA.

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http://dx.doi.org/10.1016/j.pain.2008.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705281PMC
February 2009

Evidence for a role of connexin 43 in trigeminal pain using RNA interference in vivo.

J Neurophysiol 2008 Dec 20;100(6):3064-73. Epub 2008 Aug 20.

Department of Anatomy, University of California San Francisco, San Francisco, CA 95143-0452, USA.

The importance of glial cells in the generation and maintenance of neuropathic pain is becoming widely accepted. We examined the role of glial-specific gap junctions in nociception in the rat trigeminal ganglion in nerve-injured and -uninjured states. The connexin 43 (Cx43) gap-junction subunit was found to be confined to the satellite glial cells (SGCs) that tightly envelop primary sensory neurons in the trigeminal ganglion and we therefore used Cx43 RNA interference (RNAi) to alter gap-junction function in SGCs. Using behavioral evaluation, together with immunocytochemical and Western blot monitoring, we show that Cx43 increased in the trigeminal ganglion in rats with a chronic constriction injury (CCI) of the infraorbital nerve. Reducing Cx43 expression using RNAi in CCI rats reduced painlike behavior, whereas in non-CCI rats, reducing Cx43 expression increased painlike behavior. The degree of painlike behavior in CCI rats and intact, Cx43-silenced rats was similar. Our results support previous suggestions that increases in glial gap junctions after nerve injury increases nociceptive behavior but paradoxically the reduction of gap junctions in normal ganglia also increases nociceptive behavior, possibly a reflection of the multiple functions performed by glia.
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http://dx.doi.org/10.1152/jn.90722.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2604845PMC
December 2008

Satellite glial cells in the trigeminal ganglion as a determinant of orofacial neuropathic pain.

Neuron Glia Biol 2006 Nov;2(4):247-57

Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0485, USA.

Satellite glial cells (SGCs) tightly envelop the perikarya of primary sensory neurons in peripheral ganglion and are identified by their morphology and the presence of proteins not found in ganglion neurons. These SGC-unique proteins include the inwardly rectifying K(+) channel Kir4.1, the connexin-43 (Cx43) subunit of gap junctions, the purinergic receptor P2Y4 and soluble guanylate cyclase. We also present evidence that the small-conductance Ca(2+)-activated K(+) channel SK3 is present only in SGCs and that SGCs divide following nerve injury. All the above proteins are involved, either directly or indirectly, in potassium ion (K(+)) buffering and, thus, can influence the level of neuronal excitability, which, in turn, has been associated with neuropathic pain conditions. We used in vivo RNA interference to reduce the expression of Cx43 (present only in SGCs) in the rat trigeminal ganglion and show that this results in the development of spontaneous pain behavior. The pain behavior is present only when Cx43 is reduced and returns to normal when Cx43 concentrations are restored. This finding shows that perturbation of a single SGC-specific protein is sufficient to induce pain responses and demonstrates the importance of PNS glial cell activity in the pathophysiology of neuropathic pain.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2435170PMC
http://dx.doi.org/10.1017/s1740925x07000427DOI Listing
November 2006

Chronic constriction injury of the infraorbital nerve in the rat using modified syringe needle.

J Neurosci Methods 2008 Jul 22;172(1):43-7. Epub 2008 Apr 22.

Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, United States.

Here we report a method for performing a chronic constriction injury (CCI) of the infraorbital nerve (ION) in the rat as a component of a chronic pain model. The surgical approach to the ION is described together with the use of a modified dental syringe needle that simplifies placing two chromic gut ligatures around the ION. This method makes the surgical procedure easier, the nerve injury more consistent across animals and reduces secondary damage to the ION and surrounding tissue. Pain behavior testing together with immunostaining for markers of nerve injury in the spinal trigeminal nucleus show the suitability of this procedure as a model of orofacial pain.
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http://dx.doi.org/10.1016/j.jneumeth.2008.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2497464PMC
July 2008

Silencing the Kir4.1 potassium channel subunit in satellite glial cells of the rat trigeminal ganglion results in pain-like behavior in the absence of nerve injury.

J Neurosci 2008 Apr;28(16):4161-71

Department of Neurosurgery and Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

Growing evidence suggests that changes in the ion buffering capacity of glial cells can give rise to neuropathic pain. In the CNS, potassium ion (K+) buffering is dependent on the glia-specific inward rectifying K+ channel Kir4.1. We recently reported that the satellite glial cells that surround primary sensory neurons located in sensory ganglia of the peripheral nervous system also express Kir4.1, whereas the neurons do not. In the present study, we show that, in the rat trigeminal ganglion, the location of the primary sensory neurons for face sensation, specific silencing of Kir4.1 using RNA interference leads to spontaneous and evoked facial pain-like behavior in freely moving rats. We also show that Kir4.1 in the trigeminal ganglion is reduced after chronic constriction injury of the infraorbital nerve. These findings suggests that neuropathic pain can result from a change in expression of a single K+ channel in peripheral glial cells, raising the possibility of targeting Kir4.1 to treat pain in general and particularly neuropathic pain that occurs in the absence of nerve injury.
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http://dx.doi.org/10.1523/JNEUROSCI.5053-07.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533133PMC
April 2008

Insular hypometabolism in a patient with fibromyalgia: a case study.

Pain Med 2008 Apr;9(3):365-70

Department of Family Medicine, Louisiana State University Health Sciences Center-Shreveport, Louisiana 71103, USA.

Background: Neuroimaging studies have demonstrated differential involvement of a variety of brain centers in fibromyalgia both at baseline and in response to stimulation. The insular cortex is one such structure.

Findings: A 46-year-old woman with chronic widespread pain underwent positron emission tomography utilizing 18F-fluorodeoxyglucose while participating as a healthy control subject in a brain imaging study. Analysis of the scan revealed metabolic hypoactivity within the left insular cortex as an incidental finding. Soon after her scan, she underwent further clinical evaluation and was subsequently diagnosed with fibromyalgia.

Discussion: The potential contribution of insular dysfunction to the development of hyperalgesia has been demonstrated in rat models via local manipulations of dopaminergic, gamma-aminobutyric acid (GABA) ergic, and opioidergic neurotransmission within this region. Thus, our demonstration of insular hypometabolism in this patient's case may have bearing on her experience of chronic widespread pain.
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http://dx.doi.org/10.1111/j.1526-4637.2006.00198.xDOI Listing
April 2008

Noradrenaline is necessary for the hedonic properties of addictive drugs.

Vascul Pharmacol 2006 Oct 7;45(4):243-50. Epub 2006 Jul 7.

Department of Neurological Surgery and W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA.

To determine whether noradrenaline (NA) is an essential neurotransmitter for addictive and appetitive behaviors, we measured drug and food seeking in transgenic mice lacking dopamine beta-hydroxylase (Dbh), the enzyme responsible for synthesizing NA. Using the conditioned place preference test (CPP), we show that Dbh -/- mice do not exhibit rewarding behavior to morphine, cocaine, or the mixed reuptake inhibitor bupropion. In spite of their lack of preference for drugs, Dbh -/- mice had an unaltered preference for food. Drug seeking was induced when NA was restored to the central nervous system of Dbh -/- mice by administration of l-threo-3,4-dihydroxyphenylserine (DOPS) and carbidopa. When a NK1 receptor antagonist was co-administered with morphine or cocaine, it produced aversive behavior in Dbh -/- mice while it abolished place preference in the controls. NK1 antagonists alone did not have any rewarding or aversive effect in the CPP suggesting that substance P opposes some of the unpleasant effects of morphine and cocaine. Our results show that NAergic transmission is necessary for motivated behaviors, the dysregulation of which is a co-morbid factor of many depressive states. The reversibility of this phenomenon, by restoring NA, indicates that even when this behavioral deficit is genetically determined it can be reversed.
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http://dx.doi.org/10.1016/j.vph.2005.08.030DOI Listing
October 2006

Analgesia and hyperalgesia from CRF receptor modulation in the central nervous system of Fischer and Lewis rats.

Pain 2006 Apr 21;121(3):241-260. Epub 2006 Feb 21.

Department of Neurological Surgery and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA Department of Anatomy and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA Department of Internal Medicine, Division of Rheumatology, University of Michigan Health System, Ann Arbor, MI 48109-0723, USA.

This study examines the contribution of central corticotropin-releasing factor (CRF) to pain behavior. CRF is the principal modulator of the hypothalamo-pituitary-adrenal (HPA) axis, in addition to acting on many other areas of the central nervous system. We compared nociceptive thresholds (heat and mechanical) and pain behavior in response to a sustained stimulus (formalin test) between Fischer and Lewis rats that have different HPA axis activity. Intracerebroventricular (i.c.v.) administration of CRF produced dose-dependent antinociception at a lower dose in Lewis (40 ng, paw pinch 71+/-0 g) compared to Fischer rats (200 ng, 112+/-3 g). The antinociceptive effect of CRF was mostly preserved in adrenalectomized Fischer rats. The i.c.v. administration of the CRF receptor antagonist, astressin, had a hyperalgesic effect, suggesting that CRF is tonically active. Lewis rats required higher doses of astressin (5 ng, paw pinch 51+/-1 g) to show nociceptive effects compared to Fischer rats (1 ng, 79+/-1 g). Only Lewis rats vocalized during mechanical stimulus, and this behavior was prevented by diazepam or morphine but was worsened by CRF, despite its antinociceptive property. In the formalin test, CRF and astressin had the largest effect on the interphase suggesting that they act on the endogenous pain inhibitory system. CRF also increased anxiety/fear-like behaviors in the forced swim and predator odor tests. Our results establish that central CRF is a key modulator of pain behavior and indicates that CRF effects on nociception are largely independent of its mood modulating effect as well as its control of the HPA axis.
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http://dx.doi.org/10.1016/j.pain.2005.12.024DOI Listing
April 2006

The analgesic effect of low dose focal irradiation in a mouse model of bone cancer is associated with spinal changes in neuro-mediators of nociception.

Pain 2006 Jan 19;120(1-2):188-201. Epub 2005 Dec 19.

Department of Anatomy, University of California San Francisco, San Francisco, CA 94143-0452, USA Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA Departments of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA Departments of Neuroscience, Pharmacology and Dermatology, University of Minnesota, St. Paul, MN 55108, USA.

Despite the widespread use of radiotherapy to treat painful bone metastases, the mechanism underlying the analgesic effect of low dose ionizing radiation is unknown. Bone cancer pain is mostly associated with an inflammatory response dominated by local activation of osteoclasts and by astrogliosis in the spinal cord. We determined the effects of a 6 Gy irradiation given focally on osteolytic sarcoma cells inoculated in humeri of mice. Pain behavior was assessed using the rota-rod and the grip force test. Seven days post-irradiation (day 17 post-tumor implantation) the performance of mice markedly improved on the rotarod (non-irradiated, 67+/-16s vs irradiated, 223 +/- 22 s; P = 0.0005), and the grip force test (non-irradiated, 34 +/- 4 g vs irradiated, 55 +/- 2 g; P = 0.001). This improvement was similar to the analgesia achieved with 30 mg/kg of the cyclooxygenase (COX) inhibitor ketorolac (Rota-rod, 67 +/- 16 s vs 178 +/- 35 s; P = 0.01: grip force test, 34 +/- 4 g, vs 60 +/- 5 g; P = 0.003). Following irradiation, the tumor mass and the number of osteoclasts did not decrease while the expression of two pro-inflammatory cytokines (monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha) increased. Tumor irradiation led to clear differences in the spinal cord. These include a decrease in glial activity (astrocytes and microglial cells) as well as pain mediators such as dynorphin, COX-2 and chemotactic cytokine receptor (CCR2). We conclude that the analgesic effect of low dose irradiation of bone cancer is associated with the alteration of nociceptive transmission in the central nervous system.
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http://dx.doi.org/10.1016/j.pain.2005.10.033DOI Listing
January 2006

Recurrent paraplegia after remyelination of the spinal cord.

J Neurosci Res 2004 Jul;77(2):277-84

Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94143-0452, USA.

We have conducted a long-term study of spinal cord morphology and motor function recovery in rats that have undergone lumbar spinal demyelination induced by the B-fragment of cholera toxin (CTB)-saporin. We found that, after the initial demyelination and paraplegia, motor function recovered and was stable for up to 9 months, after which there occurred a slow deterioration of motor function accompanied by loss of motoneurons and loss of spinal white matter. A striking morphological feature was the appearance of large spheroids of calcium in the ventral and dorsal horns and occasionally in the white matter. Motor performance deterioration occurred earlier and was more severe in rats that had been exercised on a treadmill, but the same morphological changes occurred in both exercise- and nonexercise-treated animals. Rats given treadmill exercise starting 3 weeks after toxin injection had a mean motor deficit score of 3.0 (i.e., paraplegia) at perfusion, whereas the nontreadmill-treated rats had a mean score of 1.8 (SD 0.38; n = 6; P <.05). These findings suggest that, in addition to the acute effects of the toxin-induced demyelination from which there is recovery of motor function, there are chronic irreversible effects of the toxin, or the initial demyelination, that cause a slow progressive degeneration of the spinal cord. This model might therefore be useful in studying the long-term effects of spinal insult of the type associated with conditions such as postpolio syndrome.
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http://dx.doi.org/10.1002/jnr.20143DOI Listing
July 2004

Anatomical identification of neurons responsive to nociceptive stimuli.

Methods Mol Med 2004 ;99:167-88

Department of Neurological Surgery, University of California San Francisco, USA.

We describe methods for labeling and identifying neurons within the central nervous system involved in the transmission of nociceptive stimuli. The most reliable methods are physiological identification followed by intracellular injection or immunocytochemical detection of stimulus-induced markers such as Fos. These latter strategies are used with appropriate controls to distinguish neurons activated secondarily (e.g., motor response or inhibitory neurons) by the nociceptive stimuli. Other methods include location and morphology as determined by standard cytological and tracing methods and/or the presence of specific neurochemical markers such as substance P determined by immunocytochemistry.
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http://dx.doi.org/10.1385/1-59259-770-X:167DOI Listing
June 2004

Experimental neurogenic cystitis.

Adv Exp Med Biol 2003 ;539(Pt A):319-35

Department of Neurological Surgery, University of California, San Francisco, 94143, USA.

Recent advances in basic and clinical research indicate that interstitial cystitis (IC) is a form of neurogenic inflammation, thereby opening new avenues for research into this painful disease. With this in mind, we have recently developed a rat model of neurogenic inflammation of the bladder produced by a central nervous system viral disease. As in IC, the inflammation in this model develops without direct injury or trauma to the bladder, is non-infectious, and is limited to the bladder. Our most recent studies aimed at further testing the similarity of this animal model to IC by assessing the urine content in histamine with the occurrence of mast cell degranulation in the bladder wall. We further verified for a sex difference in the occurrence of the disease. Our results showed increased levels of urine histamine and mast cell activation during the early stages of the disease. We additionally observed that females had a greater degree of plasma extravasation, while males had a greater cellular infiltration together with worse behavioral signs. Gonadectomy prevented the bladder inflammation altogether in both males and females. These findings further validate our model of neurogenic cystitis to study the neurogenic component of IC.
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http://dx.doi.org/10.1007/978-1-4419-8889-8_24DOI Listing
May 2004

Dopaminergic input to GABAergic neurons in the rostral agranular insular cortex of the rat.

J Neurocytol 2003 Feb;32(2):131-41

Departments of Anatomy and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA.

Increasing evidence shows that the rostral agranular insular cortex (RAIC) is important in the modulation of nociception in humans and rats and that dopamine and GABA appear to be key neurotransmitters in the function of this cortical region. Here we use immunocytochemistry and path tracing to examine the relationship between dopamine and GABA related elements in the RAIC of the rat. We found that the RAIC has a high density of dopamine fibers that arise principally from the ipsilateral ventral tegmental area/substantia nigra (VTA/SN) and from a different set of neurons than those that project to the medial prefrontal cortex. Within the RAIC, there are close appositions between dopamine fibers and GABAergic interneurons. One target of cortical GABA appears to be a dense band of GABAB receptor-bearing neurons located in lamina 5 of the RAIC. The GABAB receptor-bearing neurons project principally to the amygdala and nucleus accumbens with few or no projections to the medial prefrontal cortex, cingulate gyrus, the mediodorsal thalamic nucleus or contralateral RAIC. The current anatomical data, together with previous behavioral results, suggest that part of the dopaminergic modulation of the RAIC occurs through GABAergic interneurons. GABA is able to exert specific effects through its action on GABAB receptor-bearing projection neurons that target a few subcortical limbic structures. Through these connections, dopamine innervation of the RAIC is likely to affect the motivational and affective dimensions of pain.
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http://dx.doi.org/10.1023/b:neur.0000005598.09647.7fDOI Listing
February 2003

Rostral agranular insular cortex and pain areas of the central nervous system: a tract-tracing study in the rat.

J Comp Neurol 2004 Jan;468(3):425-40

Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94143, USA.

The rostral agranular insular cortex (RAIC) has recently been identified as a site where local changes in GABA and dopamine levels, or application of opioids, can alter nociceptive thresholds in awake animals. The connections of the cortex dorsal to the rhinal fissure that includes the RAIC have been examined previously, with emphasis on visceral and gustatory functions but not nociception. Here we examined the afferent and efferent connections of the RAIC with sites implicated in nociceptive processing. Sensory information from the thalamus reaches the RAIC via the submedius and central lateral nuclei and the parvicellular part of the ventral posterior nucleus. The RAIC has extensive reciprocal cortico-cortical connections with the orbital, infralimbic, and anterior cingulate cortices and with the contralateral RAIC. The amygdala, particularly the basal complex, and the nucleus accumbens are important targets of RAIC efferent fibers. Other connections include projections to lateral hypothalamus, dorsal raphe, periaqueductal gray matter, pericerulear region, rostroventral medulla, and parabrachial nuclei. The connectivity of the RAIC suggests it is involved in multiple aspects of pain behavior. Projections to the RAIC from medial thalamic nuclei are associated with motivational/affective components of pain. RAIC projections to mesolimbic/mesocortical ventral forebrain circuits are likely to participate in the sensorimotor integration of nociceptive processing, while its brainstem projections are most likely to contribute to descending pain inhibitory control.
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http://dx.doi.org/10.1002/cne.10978DOI Listing
January 2004