Posted on

Analgesic effects of the cathepsin K inhibitor L-006235 in the monosodium iodoacetate model of osteoarthritis pain

Introduction:
The mounting evidence that osteoclasts play an important role in osteoarthritis (OA)
pain lead us to investigate the effects of L-006235, a potent and selective inhibitor of cathepsin K, on pain behaviour and joint pathology in a model of OA pain.
Methods:
Effects of preventative (30 and 100 mg/kg) and therapeutic (100 mg/kg) oral dosing with L-006235 on weight-bearing asymmetry, hind paw withdrawal thresholds, cartilage and bone pathology, synovial inflammation, and drug exposure were studied in the monosodium iodoacetate rat model of OA pain.
Results:
Preventative L-006235 inhibited weight-bearing asymmetry from day 14, with this measure nearly abolished by the higher dose. In the same treatment setting, L-006235 prevented lowering of hind paw withdrawal thresholds from day 7. Exposure to L-006235 in plasma was higher for the 100 mg/kg dose, compared with 30 mg/kg. Therapeutic dosing with L-006235 from day 14 significantly inhibited weight-bearing asymmetry, compared with monosodium iodoacetate vehicle rats. Regression analysis revealed a significant interaction coefficient of the effects of L-006235 on weight-bearing asymmetry and synovitis score, but not for cartilage damage nor osteophyte scores.
Conclusion:
Our novel finding that cathepsin K inhibition is analgesic in a clinically relevant model of OA pain provides new evidence for the therapeutic potential of this target.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author. Address: Arthritis Research UK Pain Centre, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, United Kingdom. Tel.: 0115 82 30136; fax: 0115 82 30142. E-mail address: Victoria.chapman@nottingham.ac.uk (V. Chapman).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.painrpts.com).
Received May 18, 2018
Accepted August 03, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Analgesic effects of the cathepsin K inhibitor L-006235 in the monosodium iodoacetate model of osteoarthritis pain


Orginally Published At: PAIN Reports

Posted on

Granulocyte-macrophage colony-stimulating factor receptor expression in clinical pain disorder tissues and role in neuronal sensitization

Introduction:
Granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) is highly expressed in peripheral macrophages and microglia, and is involved in arthritis and cancer
pain in animal models. However, there is limited information on GM-CSFR expression in human central nervous system (CNS), peripheral nerves, or dorsal root ganglia (DRG), particularly in chronic pain conditions.
Objectives:
Immunohistochemistry was used to quantify GM-CSFR expression levels in human tissues, and functional sensory effects of GM-CSF were studied in cultured DRG neurons.
Results:
Granulocyte-macrophage colony-stimulating factor receptor was markedly increased in microglia at lesional sites of multiple sclerosis spinal cords (P = 0.01), which co-localised with macrophage marker CD68 (P = 0.009). In human DRG, GM-CSFR was expressed in a subset of small/medium diameter cells (30%) and few large cells (10%), with no significant change in avulsion-injured DRG. In peripheral nerves, there was a marked decrease in axonal GM-CSFR after chronic painful nerve injury (P = 0.004) and in painful neuromas (P = 0.0043); CD-68–positive macrophages were increased (P = 0.017) but did not appear to express GM-CSFR. Although control synovium showed absent GM-CSFR immunostaining, this was markedly increased in macrophages of painful osteoarthritis knee synovium. Granulocyte-macrophage colony-stimulating factor receptor was expressed in 17 ± 1.7% of small-/medium-sized cultured adult rat DRG neurons, and in 27 ± 3.3% of TRPV1-positive neurons. Granulocyte-macrophage colony-stimulating factor treatment sensitized capsaicin responses in vitro, which were diminished by p38 MAPK or TrkA inhibitors.
Conclusion:
Our findings support GM-CSFR as a therapeutic target for pain and hypersensitivity in clinical CNS and peripheral inflammatory conditions. Although GM-CSFR was decreased in chronic painful injured peripheral nerves, it could mediate CNS neuroinflammatory effects, which deserves study.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Corresponding author. Address: Peripheral Neuropathy Unit, Area A, Hammersmith Hospital, Du Cane Rd, London W12 0NN, United Kingdom. Tel.: 00 44 20 8383 3309; fax: 00 44 20 8383 3363. E-mail address: p.anand@imperial.ac.uk (P. Anand).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.painrpts.com).
Received February 23, 2018
Received in revised form June 25, 2018
Accepted July 06, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Granulocyte-macrophage colony-stimulating factor receptor expression in clinical pain disorder tissues and role in neuronal sensitization


Orginally Published At: PAIN Reports

Posted on

Heme oxygenase-1 inducer and carbon monoxide–releasing molecule enhance the effects of gabapentinoids by modulating glial activation during neuropathic pain in mice

Introduction:
Neuropathic
pain is one of the most difficult-to-treat symptoms. Although gabapentinoids are classified as first-line drugs, they have only modest efficacy.
Objectives:
The aim of this study was to investigate whether treatment with the heme oxygenase-1 (HO-1) inducer cobalt protoporphyrin IX (CoPP) or the carbon monoxide–releasing molecule tricarbonyldichlororuthenium (II) dimer (CORM-2) can enhance the antinociceptive effects produced by gabapentinoids in mice with neuropathic pain.
Methods:
Neuropathic pain was induced by spared nerve injury (SNI) of the sciatic nerve. The mechanical threshold was tested using von Frey filaments. The expression of spinal HO-1, HO-2, the Ca2+ channel α2δ1 subunit, microglial markers, and M1 or M2 microglial markers was examined using reverse transcription polymerase chain reaction.
Results:
Treatment with CoPP or CORM-2 alleviated mechanical allodynia induced by SNI. CoPP or CORM-2 enhanced the antiallodynic effects of gabapentinoids (pregabalin or gabapentin) during SNI-induced mechanical allodynia. HO-1 inhibitor tin protoporphyrin IX (SnPP) prevented the antiallodynic effects of gabapentinoids (pregabalin or gabapentin) during SNI-induced mechanical allodynia. CoPP or CORM-2 increased HO-1 and Ca2+ channel α2δ1 subunit gene expression and the decreased gene expression of microglial markers, M1 microglial marker, or tumor necrosis factor in the ipsilateral spinal dorsal horn of mice with SNI. SnPP prevented HO-1 induction and glial inhibition, which were produced by gabapentinoids during SNI-induced mechanical allodynia.
Conclusions:
This study suggests that HO-1 plays crucial roles in the antiallodynic effects of gabapentinoids. Gabapentinoids attenuate the glial activation induced by SNI and some of these effects are mediated by HO-1.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author. Address: Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. Tel.: +81-99-275-5430; fax: +81-99-265-1642. E-mail address: kxg179@icloud.com (K. Godai).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received January 30, 2018
Received in revised form July 02, 2018
Accepted July 06, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Heme oxygenase-1 inducer and carbon monoxide–releasing molecule enhance the effects of gabapentinoids by modulating glial activation during neuropathic pain in mice


Orginally Published At: PAIN Reports

Posted on

Pain relief by supraspinal gabapentin requires descending noradrenergic inhibitory controls

Introduction:
Gabapentin regulates
pain processing by direct action on primary afferent nociceptors and dorsal horn nociresponsive neurons. Through an action at supraspinal levels, gabapentin also engages descending noradrenergic inhibitory controls that indirectly regulate spinal cord pain processing. Although direct injection of gabapentin into the anterior cingulate cortex provides pain relief independent of descending inhibitory controls, it remains unclear whether that effect is representative of what occurs when gabapentin interacts at multiple brain loci, eg, after intracerebroventricular (i.c.v.) injection.
Methods:
We administered gabapentin i.c.v. in a mouse model of chemotherapy (paclitaxel)-induced neuropathic pain. To distinguish spinal from supraspinally processed features of the pain experience, we examined mechanical hypersensitivity and assessed relief of pain aversiveness using an analgesia-induced conditioned place preference paradigm.
Results:
Paclitaxel-treated mice showed a preference for a 100-μg i.c.v. gabapentin-paired chamber that was accompanied by reduced mechanical allodynia, indicative of concurrent engagement of descending controls. As expected, the same dose in uninjured mice did not induce place preference, demonstrating that gabapentin, unlike morphine, is not inherently rewarding. Furthermore, a lower dose of supraspinal gabapentin (30 μg), which did not reverse mechanical allodynia, did not induce conditioned place preference. Finally, concurrent injections of i.c.v. gabapentin (100 μg) and intrathecal yohimbine, an α2-receptor antagonist, blocked preference for the gabapentin-paired chamber.
Conclusion:
We conclude that pain relief, namely a reduction of pain aversiveness, induced by supraspinal gabapentin administered by an i.c.v. route is secondary to its activation of descending noradrenergic inhibitory controls that block transmission of the “pain” message from the spinal cord to the brain.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author. Address: Department of Anatomy, University of California, San Francisco, 1550 4th St, Rock Hall, Room 345, San Francisco, CA 94158. Tel.: (415) 502-1399. E-mail address: allan.basbaum@ucsf.edu (A.I. Basbaum).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received January 24, 2018
Received in revised form April 11, 2018
Accepted April 13, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Pain relief by supraspinal gabapentin requires descending noradrenergic inhibitory controls


Orginally Published At: PAIN Reports

Posted on

Acute hyperalgesia and delayed dry eye after corneal abrasion injury

Introduction:
Corneal nerves mediate
pain from the ocular surface, lacrimation, and blinking, all of which protect corneal surface homeostasis and help preserve vision. Because pain, lacrimation and blinking are rarely assessed at the same time, it is not known whether these responses and their underlying mechanisms have similar temporal dynamics after acute corneal injury.
Methods:
We examined changes in corneal nerve density, evoked and spontaneous pain, and ocular homeostasis in Sprague-Dawley male rats after a superficial epithelial injury with heptanol. We also measured changes in calcitonin gene-related peptide (CGRP), which has been implicated in both pain and epithelial repair.
Results:
Hyperalgesia was seen 24 hours after abrasion injury, while basal tear production was normal. One week after abrasion injury, pain responses had returned to baseline levels and dry eye symptoms emerged. There was no correlation between epithelial nerve density and pain responses. Expression of both ATF3 (a nerve injury marker) and CGRP increased in trigeminal ganglia 24 hours after injury when hyperalgesia was seen, and returned to normal one week later when pain behavior was normal. These molecular changes were absent in the contralateral ganglion, despite reductions in corneal epithelial nerve density in the uninjured eye. By contrast, CGRP was upregulated in peripheral corneal endings 1 week after injury, when dry eye symptoms emerged.
Conclusion:
Our results demonstrate dynamic trafficking of CGRP within trigeminal sensory nerves following corneal injury, with elevations in the ganglion correlated with pain behaviors and elevations in peripheral endings correlated with dry eye symptoms.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Corresponding author. Address: Department of Physiology and Pharmacology, Oregon Health & Science University, Mail code: L334, 3181 SW Sam Jackson Park Rd, Portland, OR 97239-3098. Tel.: 503-418-2550; fax: 503-494-4352. E-mail address: aichers@ohsu.edu (S.A. Aicher).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received February 27, 2018
Received in revised form April 12, 2018
Accepted April 28, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Acute hyperalgesia and delayed dry eye after corneal abrasion injury


Orginally Published At: PAIN Reports

Posted on

Inflammatory-induced spinal dorsal horn neurons hyperexcitability is mediated by P2X4 receptors

Introduction:
Purinergic ionotropic P2X receptors (P2RX) are involved in normal and pathological
pain transmission. Among them, P2X4 are expressed in dorsal root ganglion and in the spinal cord. Their activation during nerve injury or chronic peripheral inflammation modifies pain sensitivity that leads to the phenomenon of allodynia and hyperalgesia.
Objectives:
We study here, in vivo, the role of P2X4 on the excitability of dorsal horn neurons (DHNs) in naive or pathological context.
Methods:
We recorded DHNs in vivo in anesthetized wild-type or P2RX4−/− mice. We measured nociceptive integration and short-term sensitization by DHNs both in naive and inflamed mice.
Results:
Our results indicate that P2X4 alter neuronal excitability only in the pathological context of peripheral inflammation. Consequently, excitability of DHNs from inflamed P2RX4−/− mice remains similar to naive animals.
Conclusion:
These results confirm the prominent role of P2X4 in inflammatory pain context and demonstrate that P2X4 are also involved in the hyperexcitability of DHNs.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author. Address: Institut interdisciplinaire des neurosciences (IINS), Université de Bordeaux, CNRS UMR 5297, Centre Broca Nouvelle Aquitaine, 146 rue Léo Saignat, 33077, Bordeaux cedex, France. Tel.: (+33) 533514767. E-mail address: pascal.fossat@u-bordeaux.fr. (P. Fossat).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
All authors have no conflict of interest to declare.
L. Ulmann and P. Fossat share seniority.
Received January 27, 2018
Received in revised form April 13, 2018
Accepted April 17, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Inflammatory-induced spinal dorsal horn neurons hyperexcitability is mediated by P2X4 receptors


Orginally Published At: PAIN Reports

Posted on

Reduced intraepidermal nerve fibre density, glial activation, and sensory changes in HIV type-1 Tat-expressing female mice: involvement of Tat during early stages of HIV-associated painful sensory neuropathy

Introduction:
HIV infection is associated with chronic
pain states, including sensory neuropathy, which affects greater than 40% of patients.
Objectives and Methods:
To determine the impact of HIV-Tat induction on nociceptive behaviour in female mice conditionally expressing HIV Tat1-86 protein through a doxycycline (DOX)-driven glial fibrillary acidic protein promoter, intraepidermal nerve fibre density and immune cell activation in the dorsal root ganglion (DRG) and spinal cord were assessed by immunohistochemistry. Mice were assessed for mechanical and thermal sensitivity for 9 weeks using von-Frey and Hargreaves tests.
Results:
Intraepidermal nerve fibre density was significantly reduced after 6 weeks of Tat induction, similar to sensory neuropathy seen in clinical HIV infection. Tat induction through DOX caused a significant reduction in paw withdrawal thresholds in a time-dependent manner starting the 4th week after Tat induction. No changes in paw withdrawal latencies were seen in Tat(−) control mice lacking the tat transgene. Although reductions in paw withdrawal thresholds increased throughout the study, no significant change in spontaneous motor activity was observed. Spinal cord (cervical and lumbar), DRG, and hind paw skin were collected at 8 days and 6 weeks after Tat induction. HIV-Tat mRNA expression was significantly increased in lumbar DRG and skin samples 8 days after DOX treatment. Tat induced a significant increase in the number of Iba-1 positive cells at 6 weeks, but not after 8 days, of exposure. No differences in glial fibrillary acidic protein immunoreactivity were observed.
Conclusion:
These results suggest that Tat protein contributes to painful HIV-related sensory neuropathy during the initial stages of the pathogenesis.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author. Address: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA. Tel.: 1 (804) 628-7579. E-mail address: kurt.hauser@vcuhealth.org (K.F. Hauser).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
R. Wodarski and D. Bagdas contributed equally to the article as first authors. K.F. Hauser and A.S.C. Rice contributed equally to the article as senior authors.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.painjournalonline.com).
Received November 14, 2017
Received in revised form February 19, 2018
Accepted March 17, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Reduced intraepidermal nerve fibre density, glial activation, and sensory changes in HIV type-1 Tat-expressing female mice: involvement of Tat during early stages of HIV-associated painful sensory neuropathy


Orginally Published At: PAIN Reports

Posted on

Serum response factor mediates nociceptor inflammatory pain plasticity

Introduction:
Chronic metabotropic glutamate receptor activation in nociceptive afferents may upregulate A-Kinase Anchoring Protein 150 (AKAP150) expression and/or function.
Objectives:
To quantify transcriptional changes in AKAP150 expression and/or function after long-term mGluR5 agonist exposure, and identify transcriptional elements responsible.
Methods:
Dorsal root ganglia (DRG) were dissected from Sprague-Dawley rats and cultured for biochemical analysis of AKAP150 expression after prolonged mGluR5 agonist exposure. Serum response factor (SRF) expression was knocked down through siRNA in cultures to demonstrate significance to AKAP150 upregulation. Serum response factor was also knocked down in vivo through intrathecal injections of specifically targeted oligonucleotides to demonstrate significance to hyperalgesic priming behavior in persistent mechanical hypersensitivity.
Results:
Serum response factor and AKAP150 are coexpressed in TRPV1(+) DRG neurons in intact DRG. Prolonged mGluR5 agonist exposure increases SRF-dependent transcription and AKAP150 expression in a manner sensitive to protein kinase C inhibition and SRF knock down. Serum response factor in vivo knock down reduces mechanical hyperalgesic priming.
Conclusion:
Serum response factor transcription plays an important role in transcriptional upregulation of AKAP and hyperalgesic priming behavior, and may contribute to the increased role of AKAP150 in the transition from acute to chronic
pain.
This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0 (CC BY-ND) which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author.
Corresponding author. Address: Department of Oral and Maxillofacial Surgery, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229. Tel.: 210-567-3466. E-mail address: jeske@uthscsa.edu (N.A. Jeske).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.painrpts.com).
Received December 01, 2017
Received in revised form April 04, 2018
Accepted April 08, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Serum response factor mediates nociceptor inflammatory pain plasticity


Orginally Published At: PAIN Reports

Posted on

Anti–nerve growth factor therapy attenuates cutaneous hypersensitivity and musculoskeletal discomfort in mice with osteoporosis

Introduction:
The prevalence of osteoporosis is increasing with the aging population and is associated with increased risk of fracture and chronic
pain. Osteoporosis is currently treated with bisphosphonate therapy to attenuate bone loss. We previously reported that improvement in bone mineral density is not sufficient to reduce osteoporosis-related pain in an ovariectomy (OVX)-induced mouse model of osteoporosis, highlighting the need for new treatments. Targeting of nerve growth factor (NGF) with sequestering antibodies is a promising new direction for the treatment of musculoskeletal pain including back pain and arthritis. Its efficacy is currently unknown for osteoporotic pain.
Objective:
To investigate the efficacy of anti-NGF antibody therapy on osteoporotic pain in an OVX-induced mouse model.
Methods:
Ovariectomy- and sham-operated mice were injected with an anti-NGF antibody (10 mg/kg, intraperitoneally, administered 2×, 14 days apart), and the effect on behavioural indices of osteoporosis-related pain and on sensory neuron plasticity was evaluated.
Results:
Treatment with anti-NGF antibodies attenuated OVX-induced hypersensitivity to mechanical, cold, and heat stimuli on the plantar surface of the hind paw. The OVX-induced impairment in grip force strength, used here as a measure of axial discomfort, was partially reversed by anti-NGF therapy. No changes were observed in the rotarod or open-field tests for overall motor function and activity. Finally, anti-NGF treatment attenuated the increase in calcitonin gene-related peptide–immunoreactive dorsal root ganglia neurons observed in OVX mice.
Conclusion:
Taken together, these data suggest that anti-NGF antibodies may be useful in the treatment of prefracture hypersensitivity that is reported in 10% of patients with osteoporosis.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author. Address: Center for Preventive Medical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 2608670, Japan. Tel.: +81-43-226-2017; fax: +81-43-226-2016. E-mail address: miyakosuzuki170@chiba-u.jp (M. Suzuki).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received October 05, 2017
Received in revised form February 24, 2018
Accepted March 13, 2018
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Anti–nerve growth factor therapy attenuates cutaneous hypersensitivity and musculoskeletal discomfort in mice with osteoporosis


Orginally Published At: PAIN Reports