Functionally Selective Signaling for Morphine and Fentanyl Antinociception and Tolerance Mediated by the Rat Periaqueductal Gray
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{"title"=>"Functionally selective signaling for morphine and fentanyl antinociception and tolerance mediated by the rat periaqueductal gray", "type"=>"journal", "authors"=>[{"first_name"=>"Michael M.", "last_name"=>"Morgan", "scopus_author_id"=>"7403025011"}, {"first_name"=>"Rachel A.", "last_name"=>"Reid", "scopus_author_id"=>"56446241900"}, {"first_name"=>"Kimber A.", "last_name"=>"Saville", "scopus_author_id"=>"54993105900"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"600738311", "sgr"=>"84917708959", "scopus"=>"2-s2.0-84917708959", "doi"=>"10.1371/journal.pone.0114269", "issn"=>"19326203"}, "id"=>"491504ad-630a-3588-8c65-e6ebe8ef6b64", "abstract"=>"Functionally selective signaling appears to contribute to the variability in mechanisms that underlie tolerance to the antinociceptive effects of opioids. The present study tested this hypothesis by examining the contribution of G protein-coupled receptor kinase (GRK)/Protein kinase C (PKC) and C-Jun N-terminal kinase (JNK) activation on both the expression and development of tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray of the rat. Microinjection of morphine or fentanyl into the periaqueductal gray produced a dose-dependent increase in hot plate latency. Microinjection of the non-specific GRK/PKC inhibitor Ro 32-0432 into the periaqueductal gray to block mu-opioid receptor phosphorylation enhanced the antinociceptive effect of morphine but had no effect on fentanyl antinociception. Microinjection of the JNK inhibitor SP600125 had no effect on morphine or fentanyl antinociception, but blocked the expression of tolerance to repeated morphine microinjections. In contrast, a microinjection of Ro 32-0432 blocked the expression of fentanyl, but not morphine tolerance. Repeated microinjections of Ro 32-0432 blocked the development of morphine tolerance and inhibited fentanyl antinociception whether rats were tolerant or not. Repeated microinjections of SP600125 into the periaqueductal gray blocked the development of tolerance to both morphine and fentanyl microinjections. These data demonstrate that the signaling molecules that contribute to tolerance vary depending on the opioid and methodology used to assess tolerance (expression vs. development of tolerance). This signaling difference is especially clear for the expression of tolerance in which JNK contributes to morphine tolerance and GRK/PKC contributes to fentanyl tolerance.", "link"=>"http://www.mendeley.com/research/functionally-selective-signaling-morphine-fentanyl-antinociception-tolerance-mediated-rat-periaquedu", "reader_count"=>1, "reader_count_by_academic_status"=>{"Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1839594"], "description"=>"<p>Notes: N =  sample size.</p><p>*Denotes a significant difference from the vehicle control.</p><p>Effect of GRK/PKC and JNK inhibition on the Expression of Tolerance.</p>", "links"=>[], "tags"=>["Rat Periaqueductal Gray", "pkc", "grk", "JNK inhibitor SP 600125", "expression", "morphine tolerance", "fentanyl antinociception", "microinjection"], "article_id"=>1268013, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Michael M. Morgan", "Rachel A. Reid", "Kimber A. Saville"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114269.t001", "stats"=>{"downloads"=>5, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_GRK_PKC_and_JNK_inhibition_on_the_Expression_of_Tolerance_/1268013", "title"=>"Effect of GRK/PKC and JNK inhibition on the Expression of Tolerance.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-12-11 02:54:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/1839593"], "description"=>"<p>A) Repeated microinjections of morphine into the ventrolateral PAG caused tolerance as evident by a rightward shift in the morphine dose response curve (F(3,157)  = 3.689, p = .0043). Administration of the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) with morphine on Trials 1–4 prevented the development of morphine tolerance (p<.05). B) Repeated microinjections of fentanyl into the ventrolateral PAG also caused tolerance (F(3,142)  = 17.10, p = .0001). Administration of Ro 32-0432 on Trials 1–4 caused a rightward shift in the fentanyl dose-response curve whether rats were made tolerant to fentanyl or not (p<.05). C) Microinjection of the JNK inhibitor SP600125 into the ventrolateral PAG with morphine on Trials 1–4 prevented the development of morphine tolerance (F(3,142)  = 13.82, p = .0001). D) Microinjection of SP600125 (100 ng/0.4 µL) with fentanyl on Trials 1–4 prevented the development of fentanyl tolerance (F(3,137)  = 7.866, p = .0001).</p>", "links"=>[], "tags"=>["Rat Periaqueductal Gray", "pkc", "grk", "JNK inhibitor SP 600125", "expression", "morphine tolerance", "fentanyl antinociception", "microinjection"], "article_id"=>1268012, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Michael M. Morgan", "Rachel A. Reid", "Kimber A. Saville"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114269.g007", "stats"=>{"downloads"=>1, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Contribution_of_GRK_PKC_and_JNK_to_the_development_of_morphine_and_fentanyl_tolerance_/1268012", "title"=>"Contribution of GRK/PKC and JNK to the development of morphine and fentanyl tolerance.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-11 02:54:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/1839590"], "description"=>"<p>A) Microinjection of the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) into the ventrolateral PAG 20 min prior to administration of cumulative doses of morphine on Trial 5 enhanced the expression of morphine tolerance (F(1,71)  = 5.061, p = .0276). B) In contrast, microinjection of Ro 32-0432 on Trial 5 reversed the expression of fentanyl tolerance (F(1,76)  = 10.55, p = .0017). C) Microinjection of the JNK inhibitor SP600125 (100 ng/0.4 µL) on Trial 5 reversed the expression of morphine tolerance (F(1,76)  = 4.436, p = .0385), but D) had no effect on the expression of fentanyl tolerance (F(1,81)  = 0.880, p = .351).</p>", "links"=>[], "tags"=>["Rat Periaqueductal Gray", "pkc", "grk", "JNK inhibitor SP 600125", "expression", "morphine tolerance", "fentanyl antinociception", "microinjection"], "article_id"=>1268009, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Michael M. Morgan", "Rachel A. Reid", "Kimber A. Saville"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114269.g005", "stats"=>{"downloads"=>2, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_GRK_PKC_contributes_to_the_expression_of_fentanyl_tolerance_and_JNK_contributes_to_the_expression_of_morphine_tolerance_/1268009", "title"=>"GRK/PKC contributes to the expression of fentanyl tolerance, and JNK contributes to the expression of morphine tolerance.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-11 02:54:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/1839588"], "description"=>"<p>Despite different doses and test times, microinjection of morphine (tested 30 min after a dose of 5 µg, N = 32) or fentanyl (tested 3 min after a dose of 3 µg, N = 33) produced a significant increase in hot plate (HP) latency compared to saline treated controls tested 30 or 3 min after the microinjection (F(3,136) = 51.60; p = .0001).</p>", "links"=>[], "tags"=>["Rat Periaqueductal Gray", "pkc", "grk", "JNK inhibitor SP 600125", "expression", "morphine tolerance", "fentanyl antinociception", "microinjection"], "article_id"=>1268007, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Michael M. Morgan", "Rachel A. Reid", "Kimber A. Saville"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114269.g004", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Microinjection_of_morphine_and_fentanyl_into_the_ventrolateral_PAG_produced_antinociception_on_Trial_1_/1268007", "title"=>"Microinjection of morphine and fentanyl into the ventrolateral PAG produced antinociception on Trial 1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-11 02:54:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/1839587"], "description"=>"<p>Rats were injected with the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl), the JNK inhibitor SP600125 (100 ng/0.4 µL), or the appropriate vehicle into the ventrolateral PAG 20 min before microinjection of cumulative doses of morphine or fentanyl (N = 7–11/condition). Morphine or fentanyl administration produced a dose dependent increase in hot plate (HP) latency. Microinjection of Ro 32-0432 into the ventrolateral PAG enhanced the antinociceptive effect of morphine (A) as indicated by a leftward shift in the morphine dose-response curve, but had no effect on fentanyl antinociception (B). Neither morphine (C) nor fentanyl (D) antinociception were altered by microinjection of SP600125 into the ventrolateral PAG.</p>", "links"=>[], "tags"=>["Rat Periaqueductal Gray", "pkc", "grk", "JNK inhibitor SP 600125", "expression", "morphine tolerance", "fentanyl antinociception", "microinjection"], "article_id"=>1268006, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Michael M. Morgan", "Rachel A. Reid", "Kimber A. Saville"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114269.g003", "stats"=>{"downloads"=>1, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_GRK_PKC_and_JNK_inhibition_on_morphine_and_fentanyl_antinociception_/1268006", "title"=>"Analysis of GRK/PKC and JNK inhibition on morphine and fentanyl antinociception.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-11 02:54:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/1839608"], "description"=>"<div><p>Functionally selective signaling appears to contribute to the variability in mechanisms that underlie tolerance to the antinociceptive effects of opioids. The present study tested this hypothesis by examining the contribution of G protein-coupled receptor kinase (GRK)/Protein kinase C (PKC) and C-Jun N-terminal kinase (JNK) activation on both the expression and development of tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray of the rat. Microinjection of morphine or fentanyl into the periaqueductal gray produced a dose-dependent increase in hot plate latency. Microinjection of the non-specific GRK/PKC inhibitor Ro 32-0432 into the periaqueductal gray to block mu-opioid receptor phosphorylation enhanced the antinociceptive effect of morphine but had no effect on fentanyl antinociception. Microinjection of the JNK inhibitor SP600125 had no effect on morphine or fentanyl antinociception, but blocked the expression of tolerance to repeated morphine microinjections. In contrast, a microinjection of Ro 32-0432 blocked the expression of fentanyl, but not morphine tolerance. Repeated microinjections of Ro 32-0432 blocked the development of morphine tolerance and inhibited fentanyl antinociception whether rats were tolerant or not. Repeated microinjections of SP600125 into the periaqueductal gray blocked the development of tolerance to both morphine and fentanyl microinjections. These data demonstrate that the signaling molecules that contribute to tolerance vary depending on the opioid and methodology used to assess tolerance (expression vs. development of tolerance). This signaling difference is especially clear for the expression of tolerance in which JNK contributes to morphine tolerance and GRK/PKC contributes to fentanyl tolerance.</p></div>", "links"=>[], "tags"=>["Rat Periaqueductal Gray", "pkc", "grk", "JNK inhibitor SP 600125", "expression", "morphine tolerance", "fentanyl antinociception", "microinjection"], "article_id"=>1268017, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Michael M. Morgan", "Rachel A. Reid", "Kimber A. Saville"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114269", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functionally_Selective_Signaling_for_Morphine_and_Fentanyl_Antinociception_and_Tolerance_Mediated_by_the_Rat_Periaqueductal_Gray_/1268017", "title"=>"Functionally Selective Signaling for Morphine and Fentanyl Antinociception and Tolerance Mediated by the Rat Periaqueductal Gray", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-12-11 02:54:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/1839605"], "description"=>"<p>Summary of ligand-biased signaling for morphine and fentanyl antinociception and tolerance following microinjection into the ventrolateral PAG.</p>", "links"=>[], "tags"=>["Rat Periaqueductal Gray", "pkc", "grk", "JNK inhibitor SP 600125", "expression", "morphine tolerance", "fentanyl antinociception", "microinjection"], "article_id"=>1268016, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Michael M. Morgan", "Rachel A. Reid", "Kimber A. Saville"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114269.t003", "stats"=>{"downloads"=>5, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_ligand_biased_signaling_for_morphine_and_fentanyl_antinociception_and_tolerance_following_microinjection_into_the_ventrolateral_PAG_/1268016", "title"=>"Summary of ligand-biased signaling for morphine and fentanyl antinociception and tolerance following microinjection into the ventrolateral PAG.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-12-11 02:54:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/1839595"], "description"=>"<p>Notes: N =  sample size.</p><p>*Denotes a significant difference from the preceding vehicle group.</p><p>Effect of GRK/PKC and JNK inhibition on the Development of Tolerance.</p>", "links"=>[], "tags"=>["Rat Periaqueductal Gray", "pkc", "grk", "JNK inhibitor SP 600125", "expression", "morphine tolerance", "fentanyl antinociception", "microinjection"], "article_id"=>1268014, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Michael M. Morgan", "Rachel A. Reid", "Kimber A. Saville"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114269.t002", "stats"=>{"downloads"=>6, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_GRK_PKC_and_JNK_inhibition_on_the_Development_of_Tolerance_/1268014", "title"=>"Effect of GRK/PKC and JNK inhibition on the Development of Tolerance.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-12-11 02:54:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/1839591"], "description"=>"<p>A) Microinjection of morphine produced an increase in hot plate latency compared to vehicle treated controls (F(3,32)  = 8.592, p = .0003) whether rats were pretreated with the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) or not (Bonferroni, t = 0.689, n.s.). B) Likewise, fentanyl antinociception (F(3,29)  = 7.661, p = .0008) was not altered by pretreatment with Ro 32-0432 (t = 1.882, n.s.). C) Microinjection of morphine produced an increase in hot plate latency compared to vehicle treated controls (F(3,29)  = 29.67, p = .0001) whether rats were pretreated with SP600125 (100 ng/0.4 µL) or not (t = 1.942, n.s.). D) Likewise, fentanyl antinociception (F(3,28)  = 3.194, p = .041) was not altered by SP600125 pretreatment (t = 0.008, n.s.).</p>", "links"=>[], "tags"=>["Rat Periaqueductal Gray", "pkc", "grk", "JNK inhibitor SP 600125", "expression", "morphine tolerance", "fentanyl antinociception", "microinjection"], "article_id"=>1268010, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Michael M. Morgan", "Rachel A. Reid", "Kimber A. Saville"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114269.g006", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_antinociceptive_effects_of_microinjecting_morphine_or_fentanyl_into_the_ventrolateral_PAG_on_Trial_1_were_not_altered_by_blocking_activation_of_GRK_PKC_or_JNK_/1268010", "title"=>"The antinociceptive effects of microinjecting morphine or fentanyl into the ventrolateral PAG on Trial 1 were not altered by blocking activation of GRK/PKC or JNK.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-11 02:54:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/1839585"], "description"=>"<p>Morphine injections (filled squares) are shown on the left and fentanyl injections (filled circles) on the right even though all injections were administered on the right side of the PAG. The effect of the opioid was compared between rats receiving repeated opioid (closed symbols) and saline injections (open symbols). All injections were located between coronal sections 0.98 and 1.56 from the interaural line <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0114269#pone.0114269-Paxinos1\" target=\"_blank\">[20]</a>.</p>", "links"=>[], "tags"=>["Rat Periaqueductal Gray", "pkc", "grk", "JNK inhibitor SP 600125", "expression", "morphine tolerance", "fentanyl antinociception", "microinjection"], "article_id"=>1268004, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Michael M. Morgan", "Rachel A. Reid", "Kimber A. Saville"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114269.g002", "stats"=>{"downloads"=>5, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Location_of_representative_microinjection_sites_in_the_ventrolateral_PAG_/1268004", "title"=>"Location of representative microinjection sites in the ventrolateral PAG.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-11 02:54:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/1839580"], "description"=>"<p>Tolerance could be caused by a change anywhere along the signaling pathway. If this change occurs at point C in the model, then repeated co-administration of an opioid with a drug that blocks signaling at points A, B, or C will prevent the development of tolerance. Once tolerance has developed, blocking signaling at points A or B will have no effect on the expression of tolerance because signaling at point C is already altered. However, a drug that blocks the enhanced signaling from points C, D, or E will block the expression of tolerance.</p>", "links"=>[], "tags"=>["Rat Periaqueductal Gray", "pkc", "grk", "JNK inhibitor SP 600125", "expression", "morphine tolerance", "fentanyl antinociception", "microinjection"], "article_id"=>1267999, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Michael M. Morgan", "Rachel A. Reid", "Kimber A. Saville"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114269.g001", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_of_MOPr_signaling_showing_that_distinct_molecules_contribute_to_the_development_and_expression_of_opioid_tolerance_/1267999", "title"=>"Model of MOPr signaling showing that distinct molecules contribute to the development and expression of opioid tolerance.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-11 02:54:02"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"9", "full-text"=>"6", "pdf"=>"8", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"1"}
  • {"unique-ip"=>"14", "full-text"=>"13", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"3"}
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  • {"unique-ip"=>"11", "full-text"=>"11", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
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Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences", "average_usage"=>[291]}, {"subject_area"=>"/Biology and life sciences/Molecular biology", "average_usage"=>[292, 461]}, {"subject_area"=>"/Biology and life sciences/Neuroscience", "average_usage"=>[289]}, {"subject_area"=>"/Biology and life sciences/Psychology", "average_usage"=>[307]}, {"subject_area"=>"/Medicine and health sciences", "average_usage"=>[285]}, {"subject_area"=>"/Medicine and health sciences/Pain management", "average_usage"=>[277, 451]}, {"subject_area"=>"/Social sciences", "average_usage"=>[318]}]}
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