GENE EXPRESSION CHANGES IN THE BRAINSTEM AND PREFRONTAL CORTEX IN A MOUSE MODEL OF OROFACIAL PAIN POH KAY WEE (B.Sc.(Hons.), NUS) SUPERVISOR: ASSOCIATE PROFESSOR YEO JIN FEI CO-SUPERVISOR: ASSOCIATE PROFESSOR ONG WEI YI A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF ORAL AND MAXILLOFACIAL SURGERY FACULTY OF DENTISTRY NATIONAL UNIVERSITY OF SINGAPORE 2011   Acknowledgements ACKNOWLEDGEMENTS I am heartily thankful to my two supervisors, Associate Professor Yeo Jin Fei (Department of Oral and Maxillofacial Surgery, Faculty of Dentistry) and Associate Professor Ong Wei Yi (Department of Anatomy, Yong Loo Lin School of Medicine) Their encouragement, guidance and support throughout my entire candidature enabled me to develop an understanding of the subject I would like to offer my regards and blessings to all other staff members and fellow postgraduate students in Histology Laboratory, Neurobiology Programme, Centre for Life Sciences, National University of Singapore: Lee Hui Wen Lynette, Chia Wan Jie, Pan Ning, Lee Li Yen, Tang Ning, Ma May Thu, Kim Ji Hyun, Chew Wee Siong, Ee Sze Min, Loke Sau Yeen, Yap Mei Yi Alicia and Kazuhiro Tanaka for their support in any aspect during the completion of the project Lastly, I would like to thank Manikandan Jayapal and Li Zhi Hui for their guidance in microarray analysis i Table of Contents TABLE OF CONTENTS ACKNOWLEDGEMENTS i   TABLE OF CONTENTS ii   SUMMARY vi   LIST OF TABLES viii   LIST OF FIGURES ix   ABBREVIATIONS xi   PUBLICATIONS xiv   CHAPTER I INTRODUCTION   Pain   1.1 Hyperalgesia and allodynia   1.2 Neural pathways of pain   1.3 Types of pain   1.3.1 Nociceptive pain   1.3.2 Neuropathic pain   1.3.3 Inflammatory pain   1.3.4 Pyschogenic pain   1.4 Sensitization   1.4.1 Peripheral sensitization   1.4.2 Central sensitization 10   1.5 Pain pathway from the body 11   Orofacial pain 14   2.1 Trigeminal system 14   2.1.1 Trigeminal nerve 15   2.1.2 Trigeminal ganglion 16   2.1.3 Trigeminal nerve nuclei 17   2.2 Pain pathway from the orofacial region 21   2.3 Descending pain inhibitory pathway 23   Role of the brainstem in pain 26   ii Table of Contents Role of the prefrontal cortex in pain 28   Role of immune cells in pain 30   Animal models of orofacial pain 35   Use of microarrays in pain research 37   CHAPTER II EXPERIMENTAL STUDIES 41   Chapter 2.1 Gene Expression Analysis of the Brainstem in a Mouse Model of Orofacial Pain 42   Introduction 43   Materials and methods 45   2.1 Experimental animals 45   2.2 Facial carrageenan injection 45   2.3 Assessment of responses to mechanical stimulations 46   2.4 Microarray data collection and analysis 47   2.5 Real-time RT-PCR 49   2.6 Western blot analysis 50   2.7 Immunohistochemistry 51   2.8 Double immunofluorescence labeling 53   2.9 Effect of P-selectin inhibitor treatment on behavioral responses in facial carrageenan-injected mice 54   Results 56   3.1 Behavioral responses to pain after facial carrageenan injection 56   3.2 Microarray analysis 57   3.3 Validation of differentially expressed genes by real-time RT-PCR 60   3.4 Western blot analysis of P-selectin and ICAM-1 61   3.5 Immunohistochemistry of P-selectin and ICAM-1 62   3.6 Localization of P-selectin and ICAM-1 64   3.7 Effect of P-selectin inhibitor, KF38789 on nociceptive responses of carrageenan-injected mice 65   Discussion 67   Chapter 2.2 Gene expression analysis of the prefrontal cortex in a mouse model of orofacial pain 71   iii Table of Contents Introduction 72   Materials and methods 74   2.1 Experimental animals 74   2.2 Facial carrageenan injection 74   2.3 Assessment of responses to mechanical stimulations 75   2.4 Microarray data collection and analysis 75   2.5 Real-time RT-PCR 76   2.6 Western blot analysis 77   2.7 Double immunofluorescence labeling 77   2.8 Synthesis of S100A9 peptide 79   2.9 Effect of mS100A9p administration 79   2.9.1 Intracerebroventricular mS100A9p injection 80   2.9.2 Prefrontal cortex mS100A9p injection 81   2.9.3 Somatosensory cortex mS100A9p injection 81   Results 84   3.1 Microarray analysis 84   3.2 Validation of differentially expressed genes by real-time RT-PCR 88   3.2.1 Contralateral prefrontal cortex 89   3.2.2 Ipsilateral prefrontal cortex 90   3.3 Western blot analysis of S100A8, S100A9 and LCN2 92   3.4 Immunohistochemistry of S100A8, S100A9 and LCN2 93   3.5 Comparison of perfused vs non-perfused brain and findings from blood 95   3.5.1 Real-time RT-PCR findings from brain 95   3.5.2 Real-time RT-PCR findings from blood 96   3.6 Effect of mS100A9p treatment on pain behavioral responses 97   3.6.1 Intracerebroventricular mS100A9p injection 97   3.6.2 Prefrontal cortex mS100A9p injection 98   3.6.3 Somatosensory cortex mS100A9p injection 100   Discussion 101   Chapter 2.3 miRNA changes of the brainstem & PFC in a mouse model of orofacial pain 109   iv Table of Contents Introduction 110   Materials and methods 112   2.1 Experimental animals 112   2.2 Facial carrageenan injection 112   2.3 Assessment of responses to mechanical stimulations 112   2.4 Microarray data collection and analysis 112   2.4.1 Brainstem 112   2.4.2 Prefrontal cortex 113   2.5 Real-time RT-PCR 114   2.5.1 MicroRNAs 114   2.5.2 Messenger RNAs 115   2.6 Immunohistochemistry 115   Results 116   3.1 Microarray analysis 116   3.1.1 Brainstem 116   3.1.2 Prefrontal cortex 118   3.2 Validation of differentially expressed miRNAs by real-time RT-PCR 119   3.2.1 Contralateral prefrontal cortex 119   3.2.2 Ipsilateral prefrontal cortex 120   3.3 Inflammation in the prefrontal cortex 121   3.4 miRNA target prediction of mmu-miR-155, and -223 123   3.5 Targets validation of mmu-miR-155, and -223 126   3.5.1 Contralateral prefrontal cortex 126   3.5.2 Ipsilateral prefrontal cortex 127   Discussion 128   CHAPTER III CONCLUSIONS 132   CHAPTER IV REFERENCES 139   v Summary SUMMARY The brainstem and prefrontal cortex (PFC) are known to play important roles in pain, and could be involved in different phases of pain processing The brainstem is known to receive nociceptive information and involved in the descending pain inhibitory system, while the prefrontal cortex is important in the cognitive control of pain The present study was carried out using microarray-based approaches to examine gene expression and miRNA changes in the brainstem and prefrontal cortex in a mouse facial carrageenan injection model of orofacial pain At the brainstem level, increased expression of genes related to “leukocyte adhesion” i.e Selp and Icam-1 were observed in the mice brainstems three days after facial carrageenan injection It is proposed that facial carrageenan injection-induced inflammation results in the release of CCL12 into the bloodstream of the brainstem, and attracts leukocytes to the endothelial cells of blood vessel At the same time, inflammation causes upregulation of P-selectin and ICAM-1 on the surface of endothelial cells in the brainstem This facilitates transmigration of leukocytes into the brainstem or CNS, releasing pro-nociceptive substances such as nitric oxide, superoxide, or peroxynitrite, resulting in orofacial pain The use of P-selectin inhibitor, KF38789 demonstrated a decrease in pain behavioral response of facial carrageenan injected mice, possibly via the inhibition of leukocytes transmigration, and subsequent release of pro-nociceptive substances into the CNS vi Summary At the prefrontal cortex level, increased expression of miRNAs related to inflammatory diseases and immune responses i.e mmu-miR-155, and -223 were observed in the PFC three days after facial carrageenan injection Inflammation was detected in the PFC, with increased levels of MPO-positive cells observed in the PFC of mice, three days after facial carrageenan injection Inflammation in the PFC was accompanied by increased levels of immune response-related genes, including S100a8, S100a9, Lcn2, Il2rg, Fcgrl, Fcgr2b, C1qb, Ptprc, Ccl12 and Cd52 This increase in immune response may result in activation of PFC, and decrease in pain perception via the descending pain inhibitory system In addition, intracortical injection of mS100A9p into the PFC showed a decreased in pain response 12 hr after administration, suggesting an antinociceptive role of S100A9 in the PFC Together, the increased immune activity and the increased expression of S100A9 may facilitate antinociception The present studies demonstrated the involvement of both brainstem and prefrontal cortex in pain, in a mouse model of orofacial pain The differentially expressed genes in different region of the brain i.e brainstem and PFC could play different roles in pain and contribute to different part of the pain system The use of KF38789 in inhibiting P-selectin and the use of mS100A9p to mimic S100A9 in the prefrontal cortex, showed remarkable reduction in nociceptive response Thus, by targeting molecules that are involved in the pain system, it is possible to alleviate pain vii List of Tables LIST OF TABLES Table 1.1 Other pain-related terms and definitions   Table 3.1 Treatment groups for the study of P-selectin inhibitor, KF38789 on the behavioral responses in carrageenan-injected mice 55   Table 3.2 Differentially expressed genes in the ipsilateral brainstem after facial carrageenan injection 58   Table 3.3 Gene Ontology (GO) terms of the 22 common genes 59   Table 3.4 Treatment groups for the study of mS100A9p on the behavioral responses in carrageenan-injected mice 83   Table 3.5 Differentially expressed genes in the contralateral prefrontal cortex after facial carrageenan injection 86   Table 3.6 Top 20 Gene Ontology (GO) terms of the 52 common genes 88   Table 3.7 Differentially expressed miRNAs in the ipsilateral brainstems after facial carrageenan injection 117   Table 3.8 Differentially expressed miRNAs in the contralateral prefrontal cortex after facial carrageenan injection 118   Table 3.9 Gene ontology of mmu-miR-155 predicted targets 124   Table 3.10 Gene ontology of mmu-miR-223 predicted targets 125   viii List of Figures LIST OF FIGURES Figure 1.1 Diagram illustrating the changes in pain sensation induced by injury   Figure 1.2 Major pathways for pain sensation from the body 13   Figure 1.3 Diagrammatic representation of the superficial sensory distribution of the trigeminal nerve 16   Figure 1.4 Lateral view of the brainstem 18   Figure 1.5 Major pathways for pain sensation of the trigeminal system 23   Figure 1.6 Descending pain inhibitory pathway 25   Figure 3.1 Lateral view of a mouse brain 48   Figure 3.2 Diagram of a mouse brainstem 53   Figure 3.3 Responses to von Frey hair stimulation of the face after facial carrageenan injection 56   Figure 3.4 Responses to von Frey hair stimulation of the face after facial carrageenan injection 57   Figure 3.5 Real-time RT-PCR analysis of differentially expressed genes in the ipsilateral brainstem after facial carrageenan injection 60   Figure 3.6 Western blot analysis of P-selectin and ICAM-1 61   Figure 3.7 Light micrographs of the spinal trigeminal nucleus 63   Figure 3.8 Double immunofluorescence labeling with antibodies against Pselectin or ICAM-1 and vWF 64   Figure 3.9 Responses to von Frey hair stimulation of the face after tissue inflammation induced by facial carrageenan injection after daily intraperitoneal injection of P-selectin inhibitor, KF38789 66   Figure 3.10 Lateral view of a mouse brain 76   Figure 3.11 Diagram showing the sign of prefrontal cortex 79   Figure 3.12 Responses to von Frey hair stimulation of the face after facial carrageenan injection 84   Figure 3.13 Real-time RT-PCR analysis of differentially expressed genes in the contralateral prefrontal cortex after facial carrageenan injection 90   Figure 3.14 Real-time RT-PCR analysis of differentially expressed genes in the ipsilateral prefrontal cortex after facial carrageenan injection 91   ix Chapter IV References receptor CD36 may facilitate fatty acid uptake by endothelial cells 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RR (2007) Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine Brain, Behav, Immun 21:642-651         164 ... microarray-based approaches to examine gene expression and miRNA changes in the brainstem and prefrontal cortex in a mouse facial carrageenan injection model of orofacial pain At the brainstem level, increased... Inflammatory pain Tissue injury initiates an inflammatory response that induces pain This type of pain is known as inflammatory pain Inflammatory pain is due mainly to the action of prostaglandins... demonstrated the involvement of both brainstem and prefrontal cortex in pain, in a mouse model of orofacial pain The differentially expressed genes in different region of the brain i.e brainstem and