ADRB2, pain and opioids in mice and man

ADRB2, pain and opioids in mice and man 122Abstracts / Scandinavian Journal of Pain 12 (2016) 117–124ADRB2, pain and opioids in mice and manO. Kambur 1,2,∗ , A. Samoshkin 3,4 , M. Kaunisto 5 ,J.S. Wieskopf 3,6 , J.S. Mogil 3,6 , L. Diatchenko 3,4,7 ,E. Kalso 1,81Pharmacology, University of Helsinki, Faculty ofMedicine, Helsinki, Finland2 Department of Pain Research and Management,Oslo University Hospital, Oslo, Norway3 Alan Edwards Centre for Research on Pain, McGillUniversity, Montreal, QC, Canada4 Department of Anesthesia, McGill University,Montreal, QC, Canada5 Institute for Molecular Medicine Finland (FIMM),University of Helsinki, Helsinki, Finland6 Department of Psychology, McGill University,Montreal, QC, Canada7 Faculty of Dentistry, McGill University, McGillUniversity, Montreal, QC, H3A 1G1, Canada8 Helsinki University Central Hospital (HUCH), PainClinic, Helsinki, FinlandE-mail address: oleg.kambur@gmail.com (O. Kambur).Aims. We aim to characterize the effects of variation withinADRB2-gene on pain and opioid requirements in human patients.We will assess ADRB2-OPRM1-6TM heterodimer as a molecularmechanism, potentially explaining pronociceptive and antianalgetic effects, using preclinical in vitro and in vivo models. We willfurther assess clinical significance via its genetic proxy, rs563649in humans.Methods. In humans, experimental and postoperative painand opioid responses were assessed in 1000 breast cancer surgery patients. Association of ADRB2 (n = 40) and OPRM1 (n = 1)polymorphisms was assessed using linear regression and analysisof variances (ANOVA). In vitro methods involved immunofluorescence microscopy (IF), cellular localization and translocationof 6TM/␤2AR-heterodimers and Ca2+ -measurements. Behavioralin vivo characterization was performed in mice using formalin, vonFrey, hot plate and cold plate tests after administration of morphine, specific OPRM1-6TM agonist IBNtxA and ADRB2-antagonistICI118,551.Results. In humans, several ADRB2 SNPs were associated withpain and opioid phenotypes. The strongest associations were seenbetween cold pain phenotypes and rs17108817 & rs11957757(p < 0.0001). In vitro, coexpression with ␤2 -Ars increased translocation of 6TM-MOR to plasma membrane and Ca2+ responses aftertreatment with selective 6TM-agonist, IBNtxA, compared with thecells expressing OPRM1-6TM alone. In vivo, co-administration of␤2 AR selective antagonist ICI 118,551 increased analgesic efficacyof opioids in a synergistic manner and reduced opioid-inducedhyperalgesia.Conclusions. Our findings suggest that ADRB2 and geneticvariation in ADRB2-gene are involved in the modulation of humanpain and opioid responses. 6TM-MOR/␤2 -AR heterodimerizationrepresents a molecular mechanism causing excitatory cellulareffects and sufficient explanatory potential to explain pronociceptive and antianalgesic effects. Our animal findings furtherconfirmed the concept of ␤2 -AR and 6TM-MOR interaction in vivo.We suggest that co-administration of ␤-blockers with opioidsmight increase efficacy and safety of OPRM1 agonists.http://dx.doi.org/10.1016/j.sjpain.2016.05.016Retrospective analysis of pediatric patients withCRPSL. Kiehelä ∗ , J. Pouttu, K. HamunenHelsinki University Hospital (HUH), Department ofanesthesiology and intensive care, Pain Clinic,FinlandE-mail address: lauri.kiehela@hus.fi (L. Kiehelä).Aims: The aim of the study was to describe the clinical featuresand clinical pathway of pediatric CRPS patients in HUH Children’sHospital.Methods: This retrospective study included patients admittedto the pediatric pain clinic for CRPS during six years 2008–2013.Data on time from the first symptoms to diagnosis, first appointment at the pain clinic, and symptom resolution, as well asdemographic and clinical symptoms were extracted from patientrecords.Results: Forty patients were clinically diagnosed with CRPSduring the time period without using the Budapest Criteria. 75% ofthe patients were female, median age was 12, and in 90% of the casesthe CRPS was localized in the lower extremity. The median timefrom first symptoms to the CRPS diagnosis was 8.5 weeks (range0–47), to first appointment with the pain physician 10 weeks (range2–47), and to symptom resolution 35 weeks (range 10–131). Elevenout of forty patients (27.5%) were not symptom-free at the end ofthe treatment period. Most common clinical finding was allodyniaor hyperalgesia of the afflicted area (70%).Conclusions: Compared to an earlier study performed in ourhospital (retrospective study of seven years, n = 18), the number ofpatients has more than doubled, maybe due to better awarenessof the syndrome. Our findings about demographics and localization of CRPS are in agreement with previous literature. Time toreaching diagnosis, the small number of consultations and radiographs show that CRPS is well known among pediatric orthopedicsurgeons. Many Budapest criteria that are now considered important diagnostic findings were not highly prevalent in our patients(e.g. prior trauma, color changes of skin), although patient recordswere not always clear about the findings leading to diagnosis. TheBudapest criteria should be used to standardize the diagnosis alsoin our pediatric patients.http://dx.doi.org/10.1016/j.sjpain.2016.05.017Activation of epidermal growth factor receptors(EGFRs) following disc herniation induceshyperexcitability in the pain pathwaysM. Kongstorp, A. Moen, D.P. Jacobsen, F. Haugen,A. Mahmood, J. Gjerstad ∗The National Institute of Occupational Health, Oslo,NorwayE-mail address: Johannes.Gjerstad@stami.no (J. Gjerstad).Aims: Low back pain and sciatica after disc herniation may becaused by mechanical compression of the nerve roots, but also bythe release of pro-inflammatory agents including growth factorsfrom the nucleus pulposus (NP).Methods: Here, in an animal model mimicking the clinical situation following disc herniation, CLIA protein analyses, extracellularsingle-cell recordings in the spinal dorsal horn and qPCR were performed to examine the nociceptive signaling due to disc herniation.Results: The present data demonstrated that EREG may be released from NP – and that administration of EREG onto the spinaldorsal nerve roots increased spontaneous activity in nociceptiveneurons. An up-regulation of EGFR and HER4 in the dorsal horn as http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Scandinavian Journal of Pain de Gruyter
Free
1 page

Loading next page...
1 Page
 
/lp/degruyter/adrb2-pain-and-opioids-in-mice-and-man-6bbO0Vrgvl
Publisher
De Gruyter
Copyright
© 2016 Scandinavian Association for the Study of Pain
ISSN
1877-8860
eISSN
1877-8879
D.O.I.
10.1016/j.sjpain.2016.05.016
Publisher site
See Article on Publisher Site

Abstract

122Abstracts / Scandinavian Journal of Pain 12 (2016) 117–124ADRB2, pain and opioids in mice and manO. Kambur 1,2,∗ , A. Samoshkin 3,4 , M. Kaunisto 5 ,J.S. Wieskopf 3,6 , J.S. Mogil 3,6 , L. Diatchenko 3,4,7 ,E. Kalso 1,81Pharmacology, University of Helsinki, Faculty ofMedicine, Helsinki, Finland2 Department of Pain Research and Management,Oslo University Hospital, Oslo, Norway3 Alan Edwards Centre for Research on Pain, McGillUniversity, Montreal, QC, Canada4 Department of Anesthesia, McGill University,Montreal, QC, Canada5 Institute for Molecular Medicine Finland (FIMM),University of Helsinki, Helsinki, Finland6 Department of Psychology, McGill University,Montreal, QC, Canada7 Faculty of Dentistry, McGill University, McGillUniversity, Montreal, QC, H3A 1G1, Canada8 Helsinki University Central Hospital (HUCH), PainClinic, Helsinki, FinlandE-mail address: oleg.kambur@gmail.com (O. Kambur).Aims. We aim to characterize the effects of variation withinADRB2-gene on pain and opioid requirements in human patients.We will assess ADRB2-OPRM1-6TM heterodimer as a molecularmechanism, potentially explaining pronociceptive and antianalgetic effects, using preclinical in vitro and in vivo models. We willfurther assess clinical significance via its genetic proxy, rs563649in humans.Methods. In humans, experimental and postoperative painand opioid responses were assessed in 1000 breast cancer surgery patients. Association of ADRB2 (n = 40) and OPRM1 (n = 1)polymorphisms was assessed using linear regression and analysisof variances (ANOVA). In vitro methods involved immunofluorescence microscopy (IF), cellular localization and translocationof 6TM/␤2AR-heterodimers and Ca2+ -measurements. Behavioralin vivo characterization was performed in mice using formalin, vonFrey, hot plate and cold plate tests after administration of morphine, specific OPRM1-6TM agonist IBNtxA and ADRB2-antagonistICI118,551.Results. In humans, several ADRB2 SNPs were associated withpain and opioid phenotypes. The strongest associations were seenbetween cold pain phenotypes and rs17108817 & rs11957757(p < 0.0001). In vitro, coexpression with ␤2 -Ars increased translocation of 6TM-MOR to plasma membrane and Ca2+ responses aftertreatment with selective 6TM-agonist, IBNtxA, compared with thecells expressing OPRM1-6TM alone. In vivo, co-administration of␤2 AR selective antagonist ICI 118,551 increased analgesic efficacyof opioids in a synergistic manner and reduced opioid-inducedhyperalgesia.Conclusions. Our findings suggest that ADRB2 and geneticvariation in ADRB2-gene are involved in the modulation of humanpain and opioid responses. 6TM-MOR/␤2 -AR heterodimerizationrepresents a molecular mechanism causing excitatory cellulareffects and sufficient explanatory potential to explain pronociceptive and antianalgesic effects. Our animal findings furtherconfirmed the concept of ␤2 -AR and 6TM-MOR interaction in vivo.We suggest that co-administration of ␤-blockers with opioidsmight increase efficacy and safety of OPRM1 agonists.http://dx.doi.org/10.1016/j.sjpain.2016.05.016Retrospective analysis of pediatric patients withCRPSL. Kiehelä ∗ , J. Pouttu, K. HamunenHelsinki University Hospital (HUH), Department ofanesthesiology and intensive care, Pain Clinic,FinlandE-mail address: lauri.kiehela@hus.fi (L. Kiehelä).Aims: The aim of the study was to describe the clinical featuresand clinical pathway of pediatric CRPS patients in HUH Children’sHospital.Methods: This retrospective study included patients admittedto the pediatric pain clinic for CRPS during six years 2008–2013.Data on time from the first symptoms to diagnosis, first appointment at the pain clinic, and symptom resolution, as well asdemographic and clinical symptoms were extracted from patientrecords.Results: Forty patients were clinically diagnosed with CRPSduring the time period without using the Budapest Criteria. 75% ofthe patients were female, median age was 12, and in 90% of the casesthe CRPS was localized in the lower extremity. The median timefrom first symptoms to the CRPS diagnosis was 8.5 weeks (range0–47), to first appointment with the pain physician 10 weeks (range2–47), and to symptom resolution 35 weeks (range 10–131). Elevenout of forty patients (27.5%) were not symptom-free at the end ofthe treatment period. Most common clinical finding was allodyniaor hyperalgesia of the afflicted area (70%).Conclusions: Compared to an earlier study performed in ourhospital (retrospective study of seven years, n = 18), the number ofpatients has more than doubled, maybe due to better awarenessof the syndrome. Our findings about demographics and localization of CRPS are in agreement with previous literature. Time toreaching diagnosis, the small number of consultations and radiographs show that CRPS is well known among pediatric orthopedicsurgeons. Many Budapest criteria that are now considered important diagnostic findings were not highly prevalent in our patients(e.g. prior trauma, color changes of skin), although patient recordswere not always clear about the findings leading to diagnosis. TheBudapest criteria should be used to standardize the diagnosis alsoin our pediatric patients.http://dx.doi.org/10.1016/j.sjpain.2016.05.017Activation of epidermal growth factor receptors(EGFRs) following disc herniation induceshyperexcitability in the pain pathwaysM. Kongstorp, A. Moen, D.P. Jacobsen, F. Haugen,A. Mahmood, J. Gjerstad ∗The National Institute of Occupational Health, Oslo,NorwayE-mail address: Johannes.Gjerstad@stami.no (J. Gjerstad).Aims: Low back pain and sciatica after disc herniation may becaused by mechanical compression of the nerve roots, but also bythe release of pro-inflammatory agents including growth factorsfrom the nucleus pulposus (NP).Methods: Here, in an animal model mimicking the clinical situation following disc herniation, CLIA protein analyses, extracellularsingle-cell recordings in the spinal dorsal horn and qPCR were performed to examine the nociceptive signaling due to disc herniation.Results: The present data demonstrated that EREG may be released from NP – and that administration of EREG onto the spinaldorsal nerve roots increased spontaneous activity in nociceptiveneurons. An up-regulation of EGFR and HER4 in the dorsal horn as

Journal

Scandinavian Journal of Painde Gruyter

Published: Jul 1, 2016

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off