Translational Research in Pain and Itch

Preface
Contents
Chapter 1: Assessment of Itch and Pain in Animal Models and Human Subjects
	1.1 Introduction
	1.2 Assessment of Itch in Animal Models and Human Subjects
		1.2.1 Assessment of Itch in Animal Models
			1.2.1.1 Assessment of Itch in the Nape of Mice
			1.2.1.2 Assessment of Itch in the Cheek of Mice
			1.2.1.3 Assessment of Itch in the Legs of Mice
			1.2.1.4 Assessment of Itch in the Eyes of Mice
			1.2.1.5 Assessment of Itch in the Rats
		1.2.2 Assessment of Itch in Human Subjects
			1.2.2.1 Assessment of Itch Intensity and Quality
			1.2.2.2 Defining Histamine-Dependent Itch
			1.2.2.3 Defining Histamine-Independent Itch
			1.2.2.4 Human Surrogate Models of Itch
				Electrically Evoked Itch
				Mechanically Evoked Itch
				Proteinase-Activated Receptor 2/4 (PAR)-Mediated Itch
				Mas-Related G-Protein-Coupled Receptor-Mediated Itch
	1.3 Assessment of Pain in Animal Models and Human Subjects
		1.3.1 Assessment of Pain in Animal Models
			1.3.1.1 Tests Based on Thermal Stimuli
				The Tail-Flick Test
				The Paw Withdrawal Test Using Radiant Heat
				The Hot Plate Test
				Tests Using Cold Stimuli
			1.3.1.2 Tests Based on Mechanical Stimuli
				Randall and Selitto Test
				Pricking Pain Test
				Von Frey Test
				Electronic Von Frey Hair
				Q-tip Test
			1.3.1.3 Tests Based on Spontaneous Pain-Related Behavior
				Spontaneous Foot Lifting, Biting, and Licking to Estimate the Spontaneous Pain of Rats
				Formalin Test
			1.3.1.4 Tests Based on Limb Function
				Weight-Bearing Analysis Using Incapacitance Tester or CatWalk Setup
				Posture and Gait Analysis with Stainless Steel Cylinder
				Assessment of Spontaneous Mobility with Biotelemetry System or Activity Boxes
			1.3.1.5 Tests Based on Pain Emotion and Memory
				Conditioned Place Paradigm
				Conditioned Place Aversion (CPA, Fear Based)
				Conditioned Place Preference, CPP (Award Based)
		1.3.2 Assessment of Pain in Human Subjects
			1.3.2.1 Requirements for Human Subjects for the Measurement of Pain
			1.3.2.2 Assessment of Pain in Human Subjects Using Capsaicin
	1.4 Relationship Between Animal Models and Human Subjects
		1.4.1 Similarities Between Animal Models and Human Subjects
		1.4.2 Differences Between Animal Models and Human Subjects
	1.5 Limitations of Animal Models and Human Subjects
		1.5.1 Limitations of Animal Models
		1.5.2 Limitations of Human Subjects
	1.6 Conclusion
	References
Chapter 2: Allergic Contact Dermatitis: A Model of Inflammatory Itch and Pain in Human and Mouse
	2.1 Introduction
	2.2 ACD Produced a Persistent Itch and Enhanced Stimulus- Evoked Itch and Nociceptive Sensations
	2.3 ACD Enhanced Itch- and Pain-Like Behaviors in Mice
	2.4 ACD Enhanced the Excitability of Cutaneous Mechanosensitive C-Nociceptors in Mice
	2.5 ACD Upregulates CXCR3 Chemokine Receptor Signaling in Cutaneous C-Nociceptors
	References
Chapter 3: Modulation of C-Nociceptive Activities by Inputs from Myelinated Fibers
	3.1 Introduction
	3.2 A Rapid Onset of Selective Demyelination of A-Fibers by Cobra Venom Injection
	3.3 A-Fiber Demyelination Induced Neuropathic Pain and Inflammatory Responses
	3.4 Cobra Venom Intra-Nerve Injection Induced Hyperexcitability of C-Fiber Polymodal Nociceptors
	3.5 Interruption of A-Fiber Conductivity Evoked Antidromic Activity in C-Fibers
	3.6 Dorsal Root Reflexes (DRRs) Involved in Hyperexcitability of C-Fiber Nociceptors Induced by Demyelination of A-Fibers
	References
Chapter 4: New Mechanism of Bone Cancer Pain: Tumor Tissue-Derived Endogenous Formaldehyde Induced Bone Cancer Pain via TRPV1 Activation
	4.1 Introduction
	4.2 Formaldehyde Concentration Increased in Cancer Cells and Tissues
		4.2.1 Formaldehyde Concentration Increased in Cultured MRMT-1 Cells
		4.2.2 Formaldehyde Concentration Rose in Tumor Tissues from Cancer Patients
		4.2.3 Formaldehyde Concentration Was Elevated in Tissues from Rats with Bone Cancer Pain
		4.2.4 Formaldehyde Concentration Increased in Tumors and Sera of the MRMT-1 Subcutaneous Vaccination Rats
		4.2.5 LSD1 in MRMT-1 Cells Participated in the Production of Endogenous Formaldehyde
			4.2.5.1 LSD1 Protein Expression in Cancer Cells and Tissues
			4.2.5.2 Inhibition of LSD1 Function Decreased Formaldehyde Concentration and Bone Cancer Pain
	4.3 Formaldehyde Induced Bone Cancer Pain via TRPV1 Activation
		4.3.1 Formaldehyde-Induced Bone Cancer Pain
			4.3.1.1 Formaldehyde at Low Concentration Induced Acute Pain Behaviors
			4.3.1.2 Formaldehyde Secreted by Cancer Tissues Induced Bone Destruction
			4.3.1.3 Formaldehyde Enhanced Neural Excitatory
		4.3.2 Formaldehyde Induced Pain Responses via TRPV1
			4.3.2.1 Formaldehyde Increased TRPV1 Expression in Primary Cultured DRG Neurons
			4.3.2.2 Inhibitory Effects of MAPK and PI3K Inhibitors on Formaldehyde-Induced TRPV1 Upregulation in Primary Cultured DRG Neurons
			4.3.2.3 Formaldehyde Induced Ca2+ Influx and Elicited Currents in TRPV1-CHO Cells with pH of 6.0
			4.3.2.4 Formaldehyde Induced Pain Behaviors via TRPV1 Activation
	4.4 IGF-1 Enhanced TRPV1 Function in Bone Cancer Pain (Li et al. 2014)
		4.4.1 IGF-1 Expression Increased in MRMT-1 Bone Cancer Pain Rats
		4.4.2 TRPV1 Current Density and Protein Expression Increased in DRG Neurons in MRMT-1 Bone Cancer Pain Rats
		4.4.3 TRPV1 Expression Increased as well as Functionally Enhanced in Bone Cancer Pain Rats
			4.4.3.1 Co-localization of IGF-1 Receptor and TRPV1 in DRG Neurons
			4.4.3.2 IGF-1 Incubation Increased Total and Membrane TRPV1 Protein Expression in Primary Cultured DRG Neurons
			4.4.3.3 IGF-1 Incubation Increased TRPV1 Current Density in Primary Cultured DRG Neurons
		4.4.4 IGF-1R Inhibitor Reversed Pain Behavior in Bone Cancer Pain Rats
	4.5 Conclusion
	References
Chapter 5: Neuropathic Pain: Sensory Nerve Injury or Motor Nerve Injury?
	5.1 Introduction
	5.2 Injury to Motor Fibers but Not to Sensory Fibers Often Induces Lasting Allodynia and Hyperalgesia
		5.2.1 The Differential Effects of Injury to Motor Fibers and Sensory Fibers on Peripheral Sensitization
		5.2.2 The Ectopic Discharges in Intact but Not in Injured Afferents Are Responsible for Neuropathic Pain
		5.2.3 The Ectopic Discharge Is Produced by Injury to Motor Fibers but Not to Sensory Fibers
		5.2.4 The Differential Effects of Motor Fiber Injury and Sensory Fiber Injury for the Expression of Voltage- Gated Sodium Channels in Dorsal Root Ganglion Neurons
	5.3 The Differential Effects of Injury to or Electrical Stimulation of Motor Fibers and Sensory Fibers on Central Sensitization
		5.3.1 Activation of Muscle Afferents but Not Skin Afferents Induces Late-Phase LTP in Spinal Dorsal Horn
		5.3.2 Injury to Motor Fibers May Induce Spinal LTP at C-Fiber Synapses, Indirectly
	5.4 The Motor Fiber Injury Leads to Neuropathic Pain by Upregulation of Pro-inflammatory in Pain Pathway
		5.4.1 Nav1.3 and Nav1.8 in DRG Neurons Are Upregulated by TNF-α but Downregulated by IL-10
		5.4.2 TNF-α and BDNF Are Essential for Induction of Spinal LTP at C-Fiber Synapses
		5.4.3 The Direction of Synaptic Plasticity at C-Fiber in Spinal Dorsal Horn Is Decided by Microglia
	5.5 Concluding Remarks
	References
Chapter 6: T Cells and Subsets in Neuropathic Pain
	6.1 Introduction
	6.2 Infiltration of Peripheral Immune Cells into the Nervous System
	6.3 T Cells and Distinct Subsets in Neuropathic Pain
		6.3.1 Th1 Cells
		6.3.2 Th2 Cells
		6.3.3 Th17 Cells
		6.3.4 CD8+T cells
		6.3.5 Tregs
	6.4 Different Immune Patterns in NP Between Genders
	6.5 T-Cell Interactions with Neurons and Glial Cells
	6.6 Current Therapeutic Targets and Conclusion
	References
Chapter 7: Astrocytes and Microglia in Chronic Postsurgical Pain
	7.1 Introduction
	7.2 Animal Model
	7.3 Glia in Chronic Postsurgical Pain
	7.4 Astrocytes in Chronic Postsurgical Pain
		7.4.1 Phenotypes of Astrocytes
		7.4.2 NF-κB
		7.4.3 ATP
		7.4.4 Glutamate
		7.4.5 Ion Channel
		7.4.6 Connexin 43
		7.4.7 JNK
		7.4.8 CXCR7
	7.5 Microglia in Chronic Postsurgical Pain
		7.5.1 Phenotypes of Microglia
		7.5.2 IL-1β
		7.5.3 IL-6
		7.5.4 Chemokines
		7.5.5 TNF-α
	7.6 Crosstalk
		7.6.1 C3/C3aR
		7.6.2 TLR4
	References
Chapter 8: Dorsal Spinal Modulation of Neuraxial Opioid-Induced Pruritus
	8.1 Introduction
	8.2 Neuraxial Opioids Induce Itch Through the Cross-Activation of GRPR
	8.3 Disinhibition of Neural Circuits for Neuraxial Opioid-Induced Itch
		8.3.1 Neuraxial Opioids Suppress the Activity of NPY+ Neurons
		8.3.2 Neuraxial Opioids Induce Pruritus via Pdyn+ Neuron Inhibition
	8.4 Other Mediators and Receptors Involved in Neuraxial Morphine-Induced Pruritus
	8.5 Conclusion
	References
Chapter 9: Peripheral Nociceptors as Immune Sensors in the Development of Pain and Itch
	9.1 Introduction
	9.2 Morphological Correlations Between the Peripheral Nervous System and the Immune System
	9.3 Interactions Between the Peripheral Nervous and the Immune System
	9.4 The Immune-Related Receptors in Peripheral Nociceptors
	9.5 Conclusion
	References
Chapter 10: Mas-Related G-protein-Coupled Receptors Offer Potential New Targets for Pain Therapy
	10.1 History of the Mas-Related G-protein-Coupled Receptor (Mrgpr) Family
	10.2 Distribution of Mrgpr
	10.3 Mrgpr Receptors: Potential Pain Modulators
	10.4 MrgprsA and D
	10.5 MrgprB
	10.6 MrgprC
		10.6.1 Facilitation of Pain by MrgprC in Rodents
		10.6.2 Role of MrgprC in Pain Inhibition in Rodents
	10.7 MrgprE-H
	10.8 MrgprX1
	10.9 MrgprX2
	10.10 MrgprX3 and 4
	10.11 Conclusions and Future Directions
	References
Chapter 11: Pain Modulation and the Transition from Acute to Chronic Pain
	11.1 Introduction
	11.2 The PAG and RVM as a Pain-Modulating Circuit
	11.3 Is Pain Modulation a Specific Function of the PAG-RVM System?
	11.4 Inputs to the PAG-RVM Pain-Modulating System
	11.5 RVM Plasticity in Persistent and Chronic Pain
	11.6 RVM Sensitization in Multisensory Hypersensitivity
	11.7 Conclusions
	References
Chapter 12: Update in the Treatment of Neuropathic Pain
	12.1 Introduction
	12.2 Pharmacological Treatment
	12.3 Nonpharmacological Treatment
	12.4 The Treatment of Common Neuropathic Pain
		12.4.1 Central Pain
		12.4.2 Peripheral Pain
	12.5 Conclusion
	References
Chapter 13: Mechanisms of Peripheral Sensitization in Neuropathic Pain
	13.1 Introduction
	13.2 Animal Models of Peripheral Neuropathic Pain
	13.3 Keratinocytes in Peripheral Sensitization
		13.3.1 Keratinocytes in the Detection of the Noxious Stimulus
		13.3.2 Keratinocytes in the Transduction of Pain Information
		13.3.3 Keratinocytes in the Secretion of Pain Regulators
	13.4 Primary Sensory Neurons
		13.4.1 Primary Afferent Fibers
		13.4.2 Voltage-Activated Sodium Channels in Primary Sensory Neurons
		13.4.3 Voltage-Gated Calcium Channels in Primary Sensory Neurons
		13.4.4 Other Ion Channels in Primary Sensory Neurons
	13.5 Inflammation in Peripheral Sensitization
		13.5.1 Inflammatory Mediators
		13.5.2 Inflammatory Cells
	13.6 Glia Cells in Peripheral Sensitization
	13.7 Conclusion
	References
Chapter 14: Integrated, Team-Based Chronic Pain Management: Bridges from Theory and Research to High-Quality Patient Care
	14.1 Pain Prevalence
	14.2 Defining Chronic Pain
	14.3 Goals of Chronic Pain Treatment
	14.4 Core Principles for Effective Pain Management
		14.4.1 Empathy
		14.4.2 Biopsychosocial Assessment
		14.4.3 Manage Expectations/Set Functional Goals
		14.4.4 Partner with Patients to Make Shared Medical Decisions
		14.4.5 Utilization of Targeted, Rational Polypharmacy
		14.4.6 Employ Multidisciplinary Treatment Plan
		14.4.7 Reassess Progress
	14.5 The Role of Psychology in Managing Chronic Pain
	14.6 Complementary and Integrative Care
	14.7 Summary and Conclusions
	References
Chapter 15: Advances in Long-Term/Long-Lasting Treatment of Chronic Pain
	15.1 Introduction
	15.2 The Classification of Chronic Pain
	15.3 The Mechanism of Chronic Pain
	15.4 The Conventional Treatment of Chronic Pain
	15.5 New Drug Deliveries Target Chronic Pain
		15.5.1 New Pharmaceutical Dosage Form
		15.5.2 New Materials
	15.6 New Targets: Sensory Neuron Target from the Central and Peripheral Nervous System
		15.6.1 CGRP-R
		15.6.2 TRPV1 (Capsaicin Patch)
	15.7 DRG Target
	15.8 New Mechanism
		15.8.1 Gene Therapy (AAV\Lentiviral Vectors)
		15.8.2 Stem Cells and Their Derivative Injection (Bone Marrow Stromal Cells, BMSCs)
	15.9 Conclusions and Future Perspectives
	References