Introduction to Neural Transmission and the Neural Mechanisms of Acupuncture Analgesia

Taylor C. Thorne University of North Carolina Wilmington 2016 People Try Acupuncture Therapy The and Transmission of Information

Outline of Neural Transmission

1. Introduction of the Neuron 2. Anatomy of the Neuron 3. Classification of - structural - functional 4. The Electrical/Chemical Nature of the Neuron 5. Putative 6. Classical Neurotransmitters - effects of neurotransmitters 7. Postsynaptic Receptor Types 8. Activity at the 9. Antagonistic vs. Agonistic 10.Overview: Components/Functions of the 11.The Peripheral Nervous System - To better understand the process in which acupuncture - functions it is important to first grasp the understanding - sympathetic nervous system of the nature of neural transmission (aka communication - parasympathetic nervous system between neurons) within/between the central nervous - autonomic nervous supply to organs system (CNS) and peripheral nervous system (PNS) - and plexuses 12.The 13. Systems In the Brain - - dopamine - serotonin - 14.Brain Pain Pathways Introduction: The Neuron

Facts Function • size/length • processes/transmits information via electrical- • sensory neurons can have that extend from chemical signals toes to the posterior column of the • communication between neurons occurs via • over 1.5 meters in length • has about 100 billion neurons and 100 • activity may be… trillion synapses • excitatory • each neuron has (on average) 7,000 synaptic • inhibitory connections to other neurons • modulatory • neuronal cells do not undergo cell division • neurons are the core components of: • they are generated by stem cells • the brain and spinal cord (CNS) • : largely ceases during adulthood • the ganglia of the PNS • multiple types of neurons • sensory: send signals to the CNS • motor: receive signals from the CNS • : connect neurons to other neurons Anatomy of the Neuron

• : thin structures that arise from the cell body, extending/branching multiple times to create a “dendritic tree” • the majority of input to the neuron occurs here

• Soma: the cell body • Sheath: fatty layer surrounding the responsible for providing electrical conductivity from neuron to neuron

• Axon: the cellular extension from the soma at the axon hillock • the majority of information transport occurs here • aka fiber when it is myelinated • nerve fibers bundle into fascicles • bundles of fascicles make up nerves in the PNS Classification of Neurons: Structural

• based upon polarity • Unipolar: and axon emerge from same process

• Bipolar: axon and single dendrite on opposite ends of soma

• Multipolar: two or more dendrites, separate from the axon

expand or make more relevant Classification of Neurons: Functional

• Afferent nerves: convey information from tissues/organs into the CNS • aka sensory neurons

• Interneurons: connect neurons with specific regions of CNS

http://www.scholarpedia.org/article/ Interneurons

• Efferent nerves: transmit signals from CNS to effector cells • aka motor neurons The Electrical/Chemical Nature of the Neuron

• Action Potential (AP): an all or none, propagating electrochemical signal that travels along axon activating synaptic Threshold depolarization triggers the change connections in membrane permeability, thereby • fundamental process that triggers the activating/opening ion channels release of neurotransmitters (NTs) • positive voltage threshold must be reached for AP to fire • aka “wave of depolarization”

Activating The Firing of A Neuron

• Resting Membrane Potential (RMP): -70mV

• Hyperpolarization: makes the resting membrane potential more negative

• Depolarization: makes the resting membrane potential more positive

http://www.scholarpedia.org/article/ Neuron The Electrical/Chemical Nature of the Neuron

Voltage gated Na+ ion channels open only when a critical level of depolarization occurs, then other ion channels become involved

need expansion for this slide? • voltage dependent ion channels: • altered by changes in cross membrane voltage • large changes in voltage can elicit action potential Knowledge Check

1. Describe the difference in function between sensory and motor neurons. Which type of neuron is afferent and which is efferent?

2. Does the activation of the action potential require hyperpolarization of the resting membrane potential or depolarization?

3. Which ion channel opens immediately following the period of critical depolarization during the action potential? Putative Neurotransmitters List of Neurotransmitters: Neurotransmitters: chemical 1. Agmatine 30. Pancreatic polypeptide (PP) signals released from 2. Aspartate (Asp) 31. Peptide YY (PYY) presynaptic nerve terminals 3. Glutamate (Glu) 32. Corticotropin (ACTH) into the synaptic cleft 4. Gamma-aminobutyric acid (GABA) 33. Enkephaline 5. (Gly) 34. Dynorphin • transmit signals across a 6. D-serine (Ser) 35. Endorphin (e.g. 7. Acetylcholine (Ach) 36. Orexin A (OX-A) 8. Dopamine (DA) 37. Orexin B (OX-B) ) 9. Norepinephrine (NE) 38. Secretin from one neuron to another 10.Epinephrine () (Epi) 39. Motilin neuron or cell 11.Serotonin (5-HT) 40. Glucagon 12.Melatonin (Mel) 41. Vasoactive Intestinal peptide (VIP) • synthesized from simple 13.Histamine (H) 42. Growth Hormone Releasing Factor (GRF) amino acids 14.Phenethylamine (PEA) 43. Somatostatin 15.N-methylphenethylamine (NMPEA) 44. Neurokinin A • bind to receptors in the 16.Tyramine (TYR) 45. Neurokinin B membrane on the 17.Octopamine (Oct) 46. postsynaptic side of the 18.Synephrine (Syn) 47. Bombesin 19.3-methoxytyramine (3-MT) synapse 48. Gastrin releasing peptide (GRP) 20.Tryptamine 49. Anandamide (AEA) 21.N-methyltryptamine (NMT) 50. 2-arachidonoylglycerol (2-AG) Major Neurotransmitters: 22.N-acetylaspartylglutamate (NAAG) 51. 2-arachidonyl glyceryl ether (2-AGE) • amino acids 23.Gastrin 52. N-arachidonoyl dopamine (NADA) • gasotransmitters 24.Cholecystokinin (CCK) 53. Virodhamine • monoamines 25.Vasopressin (AVP) 54. Adenosine triphosphate (ATP) • trace amines 26.Oxytocin (OT) 55. Adenosine (Ado) • peptides 27.Neurophysin I • 28.Neurophysin II purines too much info? which ones most 29. Y (NY) important - trouble finding hyperlink Classical Neurotransmitters Effects of Neurotransmitters

• Inhibitory Postsynaptic Potentials (IPSPs) • Excitatory Postsynaptic Potentials (EPSPs) • hyperpolarization OR • depolarization • decrease probability of action potential • increase probability of action potential

Depends on receptor subtype! hyperlink

Neurotransmitters Terminology Postsynaptic Effects

Acetylcholine (Ach) Cholinergic +/-

Serotonin (5-HT) Serotonergic +/-

GABA GABA-ergic -

Glutamate (Glu) Glutamatergic +

Norepinephrine (NE) Adrenergic +/-

Dopamine (DA) Dopaminergic +/-

Enkephalin/Endorphin +/-

Many other neurotransmitters are derived from precursor proteins, the so-called peptide neurotransmitters. As many as 50 different peptides have been shown to exert their effects on neural cell function. Postsynaptic Receptor Types

Ionotropic Receptors Metabotropic Receptors • aka ligand-gated ion channels • aka G-protein couple receptor • neurotransmitter binds • neurotransmitter binds • recognition by its receptor • G-protein is activated • binding of GABA to receptor • G-protein subunits or intracellular • ion channel opening messengers modulate ion channels • ions flow across membrane • ion channel opens • ions flow across membrane

Hyperlink clarify/give example Activity at the Synapse

hyperlink each # to examples of substances that work at that point - stars = hyperlinks Agonistic vs. Antagonistic

Agonistic/Antagonistic drugs interact with neurotransmitters differently…

Agonists Antagonists • mimic the effects of neurotransmitters • block the brain’s neurotransmitters • produce actions • oppose actions • two main categories • two main categories • direct-binding agonists: acts just like a neurotransmitter, • direct-acting antagonist: take up the space present on binding directly to the receptor site (allows the recipient receptors otherwise occupied by NTs (blocking the NTs to experience the effects of the drug as if released themselves from binding to receptors) directly into the brain) • example: atropine • examples: dopamine, apomorphine, nicotine • indirect-acting antagonists: inhibit the release/production • indirect-acting agonists: enhance the neurotransmitter of neurotransmitters actions by stimulating NT release • example: reserpine • example: cocaine

hyperlink Overview: Components and Functions of the Nervous System

http://www.scholarpedia.org/article/ Nervous_system Knowledge Check

1. Which classic neurotransmitter is strictly inhibitory while the others are both inhibitory and excitatory?

2. What are the differences between re-uptake and enzymatic degradation?

3. Is nerve gas an agonistic or antagonistic drug? Explain why the Ach receptor agonists works to inhibit the enzyme acetylcholinesterase. The Peripheral Nervous System (PNS)

• consists of nerves and ganglia on outside of the brain and spinal cord

• main function: connect the CNS to limbs and organs • serves as a communication relay between brain and extremities

• not protected by bone or blood-brain barrier • exposed to toxins and injury

• divided into two systems • Somatic nervous system (SNS) • Autonomic nervous system (ANS) • Sympathetic nervous system • Parasympathetic nervous system

• twelve Cranial Nerves (part of PNS and not CNS) • 10/12 originate from : mainly control functions of the ANS

• 31 pairs of Spinal Nerves: controls functions of the rest of the body • 8 cervical • 12 thoracic • 5 • 1 coccygeal Nerves and Plexuses

• Cervical plexus (C1-C4) • C1: suboccipital nerve • provides motor innervation to muscles at base of skull • C2 and C3: provide sensory and motor control • greater occipital nerve: provides sensation to back of head • lesser occipital nerve: provides sensation to area behind the ears • C3, C4 and C5 • innervates the diaphragm, enabling breathing

• Thoracic Nerves (T1-T12)

• Brachial plexus (C5-T1) • serve the upper back and upper limbs

• Lumbosacral plexus (L1-S4) • divided into three parts • lumbar plexus • sacral plexus • pudendal plexus Somatic Nervous System (SNS)

• aka “voluntary” nervous system

• associated with skeletal muscle motor control

• consists of afferent and efferent nerves

• 43 segments of nerves in the human body • each segment has a pair of motor and sensory nerves

• somatic nervous system consists of two parts • spinal nerves: peripheral nerves that carry sensory information into and motor commands out of the spinal cord • 31 segments of nerves

• cranial nerves: nerve fibers that carry information into and out of the brain stem • 12 segments of nerves • include smell, vision, eye, eye muscles, 1. (Brain) Precentral Gyrus: the origin of nerve signals initiating movement mouth, taste, ears, , shoulders, and tongue 2. (Cross Section of Spinal Cord) Corticospinal Tract: mediator of message from brain to skeletal muscles

3. Axon: messenger cell that carries the command to contract muscles

4. Neuromuscular Junction: messenger axon cell tells muscle cells to contract at this intersection Autonomic Nervous System (ANS)

• aka “control system”

• influences the function of internal organs

• (largely) unconsciously regulates bodily functions • , , respiratory rate, pupillary response, urination, and sexual arousal

• primary mechanism in “fight or flight” and “freeze and dissociate” responses

• regulated by the • receives ANS regulatory input from

• divided into two branches • Sympathetic Nervous System (SoNS) • Parasympathetic Nervous System (PaNS) • function in opposite actions, where one system activates a physiological response and the other inhibits it

• unique in that it requires a sequential two-neuron efferent pathway • preganglionic neuron must first synapse onto a postganglionic neuron before innervating the target one

• preganglionic neuron will begin outflow and will synapse at the postganglionic neuron’s cell body • postganglionic neuron will then synapse at target Autonomic Nervous System (ANS): Sympathetic Nervous System

• excitatory

• emerges from spinal cord in the thoracic and lumbar areas (terminating around L2-L3)

• consists of cells with bodies in the lateral (T1 to L2-L3) • these cell bodies are general visceral efferent neurons (GVE) and are the preganglionic neurons

• locations which preganglionic neurons can synapse for their postganglionic neurons • paravertebral ganglia • cervical ganglia • thoracic ganglia and rostral lumbar ganglia • caudal lumbar ganglia and sacral ganglia • pre vertebral ganglia • celiac , aorticorenal ganglion, superior mesenteric ganglion, inferior mesenteric ganglion • chromatic cells of the • this is the one exception to the two-neuron pathway rule (the synapse is directly efferent onto the target cell bodies)

• these ganglia provide postganglionic neurons from which innervation of target organs follows Typical Actions of the SoNS

• corresponds with arousal and energy generation

• inhibits digestion

• diverts blood flow away from GI tract and skin via

• blood flow to skeletal muscles and the lungs is enhanced (by as much as 1,200% in the case of skeletal muscles)

• dilates of the lung through circulating epinephrine (allows for greater alveolar oxygen exchange)

• increases heart rate and the contractility of cardiac cells (providing mechanism for enhanced blood flow to skeletal muscles)

• dilates pupils and relaxes ciliary muscle to the lens (allowing more light to enter the eye and far vision)

• provides vasodilation for the coronary vessels of heart

• constricts all intestinal sphincters and urinary sphincter

• inhibits peristalsis

• stimulates orgasm Autonomic Nervous System (ANS): Parasympathetic Nervous System

• parasympathetic nervous system: rest and digest, feed and breed • inhibitory • craniosacral “outflow,” meaning neurons begin at cranial nerves (oculomotor nerve, facial nerve, glossopharyngeal nerve, vagus nerve) and sacral spinal cord (S2-S4)

• consists of cells with bodies in one of two locations • brainstem (cranial nerves 3, 7, 9, and 10) • sacral spinal cord (S2-S4)

• these are preganglionic neurons which synapse with postganglionic neurons in these locations… • parasympathetic ganglion of the head • ciliary (cranial nerve 3), submandibular (cranial nerve 7), pterygopalatine (cranial nerve 7), and otic (cranial nerve 9) • in or near the wall of an organ innervated by the vagus (cranial nerve 10) or sacral nerves (S2-S4)

• these ganglia provide postganglionic neurons from which innervations of target organs follows Typical Actions of the PaNS

• calming of the nerves to return to regular function

• dilating blood vessels leading to GI tract, increasing blood flow (important following consumption of food due to greater metabolic demands placed on the body by the gut)

• constricting the bronchiolar diameter when the need for oxygen has diminished

• dedicated cardiac branches of the vagus and thoracic spinal accessory nerves impart parasympathetic control of the heart (myocardium)

• constriction of the pupil and contraction of the ciliary muscles (facilitating accommodation and allowing for closer vision)

• stimulating salivary gland secretion and accelerates peristalsis (mediating digestion of food and, indirectly, the absorption of nutrients)

• stimulates sexual arousal: erection of genital tissues via pelvic (2-4) Autonomic Nervous Supply to Organs aka “Innervation”

Organ Nerves Spinal Column Origin PS: anterior and posterior vagal trunks T6, T7, T8, T9 Stomach S: greater splanchnic nerves sometimes T10

PS: vagus nerves T5, T6, T7, T8, T9 Duodenum S: greater splanchnic nerves sometimes T10

PS: vagus nerves T8, T9 Pancreatic Head S: thoracic splanchnic nerves

PS: posterior vagal trunks T5, T6, T7, T8, T9 Jejunum and Ileum S: greater splanchnic nerves

PS: vagus nerves and pelvic splanchnic nerves T10, T11, T12 (proximal colon) Colon S: greater splanchnic nerves L1, L2, L3 (distal colon)

Spleen S: greater splanchnic nerves T6, T7, T8

Vermiform Appendix nerves to superior mesenteric plexus T10 PS: vagus nerve T6, T7, T8, T9 S: celiac plexus Gallbladder and right phrenic nerve

PS: vagus nerve T11, T12 Kidneys and Ureters S: thoracic and lumbar splanchnic nerves

PS = Parasympathetic S = Sympathetic The ANS and Neurotransmitters

At the effector organs, sympathetic ganglionic neurons release noradrenaline (norepinephrine), along with other co- transmitters (such as ATP) to act on adrenergic receptors, with the exception of the sweat glands and the adrenal medulla

- acetylcholine is the preganglionic neurotransmitter for both divisions of the ANS, as well as the postganglioninc transmitter of parasympathetic neurons - nerves that release acetylcholine are said to be cholinergic - in the parasympathetic system, ganglionic neurons use acetylcholine as a neurotransmitter to stimulate muscarinic receptors

- at the adrenal medulla, there is no postsynaptic neuron - instead, the presynaptic neuron releases acetylcholine to act on nicotinic receptors - stimulation of the adrenal medulla releases adrenaline (epinephrine) into the bloodstream, which acts on adrenoceptors, producing a widespread increase in sympathetic activity Overview: Peripheral Nervous System The Central Nervous System: The Brain and Spinal Cord

• complex of nerve tissues that controls the activities of the body

• spinal cord is continuous with the brain • consists of 33 vertebrae

• from and to the spinal cord are projections of the PNS (called spinal nerves) • allow for transmission of efferent and afferent signals and stimuli

• consists of… • gray matter: made of axons and oligodendrocytes • : made of neurons and unmyelinated fiber

needs to be more focused on literal CNS http://www.scholarpedia.org/article/ Spinal_cord Hierarchy of the CNS

Central Nervous System

Brain Spinal Cord

(Forebrain) Prosencephalon Brain Stem

() (Part of Forebrain) (Midbrain) (Hindbrain) Telencephalon Diencephalon Mesencephalon Rhombencephalon

Rhinencephalon, Epithalamus, , Tectum, Cerebral Peduncle, Mesencephalon Myelencephalon , Hypothalamus, Pretectum, Mesencephalic , Subthalamus, Pituitary Duct , Basal Gland, Pineal Gland, Ganglia, Lateral Third Ventricle Pons/Cerebellum Ventricles Knowledge Check

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3. … Neurotransmitter Systems In the Brain: Noradrenaline

Pathway Origins and Projections: Regulated Cognitive Processes and Behaviors: • (LC) projections • anxiety • LC —> Amygdala and Hippocampus • arousal (wakefulness/attention) • LC —> Brain Stem and Spinal Cord • circadian rhythm • LC —> Cerebellum • cognitive control and working memory • LC —> • co-regulated by dopamine • LC —> Hypothalamus • hunger • LC —> Tectum • medullary control of respiration • LC —> Thalamus • negative emotional memory • LC —> Ventral Tegmental Areal • reward perception • lateral tegmental field (LTF) projections • LTF —> Brain Stem and Spinal Cord • LTF —> Olfactory Bulb Neurotransmitter Systems In the Brain: Dopamine

Pathway Origins and Projections: Regulated Cognitive Processes and Behaviors: • (VTA) projections • aversion • VTA —> Amygdala • cognitive control and working memory • VTA —> Cingulate Cortex • co-regulated by norepinephrine • VTA —> Hippocampus • mood • VTA —> (mesolimbic) • reward perception (primary mediator) • VTA —> Olfactory Bulb • positive reinforcement • VTA —> (mesocortical) • motivation • • motor system function • Substantia Nigra —> / • sexual arousal, orgasm, and refractory period • tuberoinfundibular pathway • —> Hypothalamus Neurotransmitter Systems In the Brain: Origins and Projections: Regulated Cognitive Processes and Behaviors: • caudal nuclei (CN): raphe magnus, raphe pallidus, raphe obscurus • appetite satiety • caudal projections • arousal (wakefulness/attention) • CN —> Cerebral Cortex • body temperature regulation • CN —> Thalamus • emotion, mood (potentially including aggression) • CN —> Caudate Putamen/Nucleus Accumbens • reward perception • CN —> Substantia Nigra/Ventral Tegmental Area • sensory perception • rostral nuclei (RN): nucleus linearis, dorsal raphe, medial raphe • sleep • rostral projections • RN —> Amygdala • RN —> Cingulate Cortex • RN —> Hippocampus • RN —> Hypothalamus • RN —> Neocortex • RN —> Septum • RN —> Thalamus • RN —> Ventral Tegmental Area Neurotransmitter Systems In the Brain: Acetylcholine Pathway Origins and Projections: Regulated Cognitive Processes and Behaviors: • forebrain cholinergic nuclei (FCN): of • arousal (wakefulness/attention) meynert, medial septal uncles, diagonal band • emotion • forebrain nuclei projections • learning • FCN —> Hippocampus • motor system function • FCN —> Cerebral Cortex • short term memory • FCN —> Limbic Cortex/Sensory Cortex • reward perception • brainstem cholinergic nuclei (BCN): laterodorsal , medial habenula • brainstem nuclei projections • BCN —> Ventral Tegmental Area • BCN —> Thalamus The Brain and Pain

some sort of transitional slide from neural transmission into pain Major Brain Pathways of Pain

When noxious stimuli is presented to afferent nerve endings, pain signals are conducted through the spinal cord to the brainstem and processed throughout the cerebrum

• : the sensory nervous system’s response to harmful or potentially harmful stimuli Relay Stimuli: Dorsal Root Ganglion Decussation: Limbic System Input of Stimuli: Somatosensory Cortex Knowledge Check

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3. … Acupuncture What is Acupuncture?

Acupuncture: the insertion of extremely thin needles through your skin at strategic points on the body (most commonly used to treat pain)

• form of alternative medicine

• sometimes associated with application of heat, pressure, or laser light to acupoints

• different philosophies of acupuncture • Traditional Chinese medicine explains acupuncture as a technique for balancing the flow of energy (known as Qi) believed to flow through pathways (meridians) in the body • many Western practitioners view acupuncture points as places to stimulate nerves, muscles, and connective tissue (boosts body’s natural painkillers and increases blood flow)

• low risk

• benefits of acupuncture are sometimes hard to measure Putative Acupuncture Treatments

Other Conditions Treated by Acupuncture • sinusitis • earache • high blood pressure • IBS • constipation/diarrhea • food allergies • ulcers • endometriosis • morning sickness • infertility in men and women • sexual dysfunction • candida • chronic fatigue • epstein barr virus Medically Accepted Treatment For… • cigarette/drug/alcohol addiction • chemotherapy induced and • anxiety postoperative nausea and vomiting • insomnia • dental pain • depression • fibromyalgia • stress • headaches, including tension and • arthritis • asthma migraine headaches • emphysema • labor pain • bronchitis • low back pain • colds/flus • weight gain/loss • neck pain • osteoarthritis • menstrual cramps Theoretical/Physiological Basis of Acupuncture

Abstract?? Outline: Neural Mechanisms Underlying Acupuncture Analgesia

1. Main Advancements In Technology/Understanding 2. Methods of Acupuncture 3. Acupoints 4. Meridians 5. De-Qi 6. Cellular Communication: Connection Between the Brain and Body 7. Malfunctions In Neurons 8. Acupuncture Analgesia 9. Following Acupuncture Treatment Reduce/Refine/Focus as filling in slides 10.Individual Differences 11.Psychological Factors 12.Acupuncture Induced De-Qi Feeling 13.Afferent Nerve Fibers Activated by Acupuncture 14.A Result of Sensory Interaction 15.Functional Specificity of Acupoints 16.Neural Pathways 17.Relevant Brain Areas 18.Functional Imaging Studies 19.Nuclei Involved In Processing Analgesia 20.Diverse Signal Molecules 21.Roles of Transmitters and Modulators in Acupuncture Analgesia 22.Glial Function 23.Possible Molecular Mechanisms Acupoints Acupoints: Triggers of Analgesia

Peripheral Nerves vs. Acupoints • Acupoints = Acupuncture Points Similarities?

• 361 acupoints in the human body

• 323 acupoints exhibit rich innervation mainly in deep tissues

• indicates acupoints are innervated by peripheral nerves

• significantly decreased number/density of subcutaneous nerve structures compared with non-acupoints

• deep sensory receptors are located in acupoints in muscle Styles of Acupuncture

• Traditional Chinese Medicine: main focus is to • Auricular Acupuncture: points in the ear balance the body (physical, mental, emotional, correspond to areas of the body/certain spiritual well-being is optimized) disharmonies • most common method in the U.S. • commonly used for pain control and drug/ alcohol/nicotine addictions • Japanese Style Acupuncture: fewer and thinner • also a microsystem needles used with less stimulation • aka Classical Acupuncture • Medical Acupuncture: Western doctor • focuses on applying laws of the Five Element performing acupuncture Theory • main goal is cessation of pain: acupoints are selected to yield neurological responses to • Korean Acupuncture: many needles used in block pain treatment • electric stimulation often added

• Korean Hand Acupuncture: points in the hand • Veterinary Acupuncture correspond to areas of the body and to certain disharmonies • is a microsystem of acupuncture (only the hand is used to treat the whole body) Theoretical Energy Pathways: Meridians

• Meridian Theory: network systems to link acupoints via energy (De-Qi) streaming in pathways (meridians…like on a map)

• Meridians: referred to as channels and their branches where 361 acupoints are located • no evidence of existing anatomical structures of meridians (fictive lines meant to be a functional concept) • includes summation of physiological functions including… • nervous system • circulatory sustem • endocrine system • immune system

• 12 principal meridians (divided into Yin and Yang groups)

• large amount of acupoints are bilateral (361 x 2 = 722) 12 Principal Meridians

Meridian Name (Chinese) Organ Taiyin Channel of Hand Lung Shaoyin Channel of Hand Heart Jueyin Channel of Hand Pericardium • pathways extend Shaoyang Channel of Hand Triple Burner between the hands and Taiyang Channel of Hand Small Intestine the feet Yangming Channel of Hand Large Intestine • De-Qi travel bilaterally Taiyin Channel of Foot Spleen through the body Shaoyin Channel of Foot Kidney Jueyin Channel of Foot Liver Shaoyang Channel of Foot Gall Bladder Taiyang Channel of Foot Urinary Bladder Yangming Channel of Foot Stomach De-Qi

• De-Qi: local feeling of pulling and increased resistance in the acupuncturists fingers to further movement of the inserted needle • similar sensation of a fish taking bait on a line

• arrival of Qi is a healing process

• propagated sensation along meridians (PSM): De-Qi often spreads/radiates from acupoint (explained as the flow of Qi)

• clinical observation of paraplegic patients: no feeling of De-Qi in lower limbs, nor any effects in upper parts of the body • due to the involvement of somatic sensory functions in acupuncture analgesia and innervation of acupoints

• If De-Qi can not be generated, then inaccurate

location of the acupoint, improper depth of needle Significance of “Deqi” Response in insertion, inadequate manual manipulation, or a Acupuncture Treatment: Myth or Reality very weak constitution of the patient can be considered, all of which are thought to decrease the likelihood of successful treatment Cellular Communication: Connection Between the Brain and Body

what do we know what do we think Methods of Acupuncture • Manual Acupuncture (MA): needle inserted into acupoint and twisted up and down by hand • activates all types of afferent fibers • Ab fibers: 2nd most highly myelinated fibers • due to large diameter • highest conduction velocity of all nerves • Ad fibers: responsible for carrying cold, pressure, and some pain signals • thinly myelinated • C fibers: unmyelinated with smaller diameter and low conduction velocity • postganglionic fibers in the ANS • nerve fibers at dorsal roots • responsible for nociception, temperature, touch, pressure, itch

• Electrical Acupuncture (EA): stimulating current delivered to acupoints via needles connected to electrical stimulator • intense enough to excite Ab and Ad fibers • signals ascend mainly through the spinal ventrolateral finiculus to the brain • secondary method: place surface electrode on skin over acupoint • different from transcutaneous electrical nerve stimulation (TENS unit) • delivered on skin of pain region rather than acupoint Acupuncture Analgesia

• Analgesia: the relief of/inability to feel pain • the manifestation of integrative processes at different levels in the CNS between afferent impulses from pain regions and impulses from acupuncture • described as manifested only when the intricate feeling (soreness, numbness, heaviness and distention) of acupuncture in patients occurs following the insertion of needles/treatment

Complicated Network of Brain Nuclei Involved in Processing Analgesia - nucleus raphe magnus (NRM) - periaqueductal grey (PAG) - locus coereleus All - arcuate nucleus (Arc) Contribute - pre-optic area - nucleus submedius to the - habenular nucleus neurobiology - caudate nucleus of PAIN - - amygdala Mechanisms of Pain Modulation Individual Differences

• defines analgesic effect for each patient Study: Individual Differences

• study: analgesic effects of three models of acupuncture • model 1 - manual acupuncture • model 2 - electrical acupuncture • model 3 - placebo

Results: the treatment, not the placebo model, lowered pain ratings in response to noxious thermal stimuli - highly significant analgesia found in 5 to 11 subjects - 2/5 responded only to EA - the other 3 responded only to MA massively reduce what’s most important here? Psychological Factors can this be broken down into more than one slide

• inevitable for psychological factors to influence the effects of acupuncture analgesia

• increasing evidence demonstrates analgesia is predominantly attributable to its physiological rather than psychological action • effective in treating chronic pain • helps 50% to 80% of patients Study: Psychological Factors

• study: 14 patients suffering painful osteoarthritis • PET found insult ipsilateral to site of needling was activated to greater extent during acupuncture than placebo treatment • needles cause greater activation than skin prick (non-effective stimulation) in right dorsolateral prefrontal cortex, anterior cingulate cortex, and midbrain

• stimulation of hypothalamic-pituitary axis (HPA) • resulting in adrenocorticotropic hormone (ACTH) secretion: occurs in response to variety of psychological/physical stressors • study: highly anesthetized rats • EA enhanced ATCH plasma release without usual autonomic responses to psychological stress (tachycardia or blood pressure elevation) which was blocked by deprivation of afferent input • awakening rat: immobilization stress is mostly a psychological stressor • immobilization stress induced ATCH release despite deprivation of afferent input • results suggest that EA depends on physiological afferent signals elicited in the somatosensory pathway • acupuncture has a specific psychological effect and patients’ expectations/belief regarding treatment modulate activity in hypothalamic-pituitary corticotrope system During Acupuncture Treatment

• procaine: Following Acupuncture Treatment

• pain threshold increases indicating delayed development of analgesia

• lasting effect once treatment is terminated • studies: • pain threshold to eight points distributed on the head, , back, abdomen, and leg was fairly stable for over 100 minutes • LI-4 acupoint: produced increase in pain threshold with peak increase during 20 to 40 minutes after needle insertion • persisted over 30 minutes after withdrawal of needle • injection of 2% procaine prior to treatment produced neither local sensation nor analgesic effect Peripheral Mechanisms Underlying Acupuncture Analgesia

• acupuncture induced de-qi feeling

• origin from

• origin from connective tissue Afferent Nerve Fibers Activated by Acupuncture

• Ab fibers • electroacupuncture (EA) • Ad fibers • manual acupuncture (MA) • C fibers Chemical Mechanisms: Result of Sensory Interaction The Functional Specificity of Acupoints Neural Pathways

• two leading ascending pain pathways • spinoparabrachial tract • spinothalamic tract Relevant Brain Areas

• endogenous descending inhibitory system in CNS: valuable for understanding pain • rostal ventromedial medulla (RVM) • nucleus raphe magnus (NRM) • periaqueductal grey (PAG) • locus coeruleus (LC) • arcuate nuclei (Arc)

• brain structures involved in modulation of acupuncture analgesia • mainly the RVM • PAG • LC • Arc • pre optic area (Po) • centromedian nucleus (CM) • nucleus submedius (Sm) • anterior pretectal nucleus (APtN) • habenular nucleus (Hab) • nucleus accumbens (Ac) • caudate nucleus (Cd) • septal area (Sp) • amygdalae • anterior cingulate cortex (ACC) • hypothalamic paraventricular nucleus (PVH) Functional Imaging Studies Nuclei Involved In Processing Analgesia Nucleus Raphe Magnus (NRM)

• located in the central reticular formation of the medulla oblongata

• receives input from spinal cord and cerebellum (motor system)

• plays paramount role in homeostatic regulation (mainly pain regulation)

• receives descending afferents from PAG matter, the paraventricular hypothalamic nucleus, central nucleus of the amygdala, lateral hypothalamic area, parvocellular reticular nucleus, and the pre-limbic, infra-limbic, medial and lateral pre-central cortices • PAG sends efferent connections to the NRM when • sends projections to dorsal horn of spinal cord to directly stimulated by opiates inhibit pain • PAG or NRM then receive morphine upon electrical stimulation • releases serotonin when stimulated • afferent fibers from the spinothalamic tract synapse at the • raphe spinal neurons project to enkephalin releasing PAG which is linked to NRM interneurons in the posterior horn of spinal cord • when NRM is stimulated it directly inhibits pain fibers in dorsal horn of spinal cord, thus alleviating pain • all part of an endogenous opiate system Periaqueductal Grey (PAG)

• produces analgesic effect when electrically stimulated • sends efferent connections to the NRM when stimulated by opiates • followed by administration of morphine

• afferent fibers from the spinothalamic tract synapse at the PAG which is linked to the NRM • NRM stimulated • inhibits pain fibers • alleviates pain Locus Coereleus Arcuate Nucleus (Arc) Pre-optic Area Nucleus Submedius Habenular Nucleus Accumbens Nucleus Caudate Nucleus Septal Area Amygdala Diverse Signal Molecules

• opioid peptides • m receptors • d receptors • k receptors - opioid peptides/receptors in Arc-PAG-NRM spinal dorsal horn pathway play pivotal role in mediating analgesia - release of opioid peptides evoked by EA is frequency based

• glutamate • NMDA receptor • AMPA/KA receptor

• 5-HT

• CCK-8 - antagonizes analgesia - individual differences in analgesia are associated with inherited genetic factors and the density of CCK receptors Opioid Peptides

• m receptors

• d receptors

• k receptors

Opioid peptides and receptors in Arc-PAG-NRM spinal dorsal horn pathway play pivotal role in mediating analgesia - release of opioid peptides evoked by EA is frequency based Glutamate

• NMDA receptor

• AMPA/KA receptor 5-Hydroxytryptamine (5-HT) Cholecystokinin Octapeptide (CCK-8)

• antagonizes analgesia • individual differences in analgesia are associated with inherited genetic factors and the density of CCK receptors Roles of Transmitters and Modulators in Acupuncture Analgesia

• opioid peptides • peripheral opioid peptides • central opioid peptides • CCK-8 • 5-HT • noradrenalin (NA) • glutamate and its receptors • GABA • GABAa receptor • GABAb receptor • other bioactive substances Opioid Peptides Cholecystokinin Octapeptide (CCK-8) 5-Hydroxytryptamine (5-HT) Noradrenaline (NA) Glutamate and Its Receptors g-Amino-Butyric Acid (GABA) Other Bioactive Substances

• substance P (SP) • angiotensin II (AII) • somatostatin (SOM) • arginine vasopressin (APV) • neurotensin (NT) • dopamine (DA) Glial Function Possible Molecular Mechanisms Conclusion/Closing Malfunction in Neurons

MS, Alzheimer’s and Parkinson’s: common neurological diseases that are caused by/lead to the demyelination and axonal degeneration of the neurons responsible for associated areas of the brain

Question: could acupuncture treatment provide results for patients who suffer neurodegenerative diseases which would, in theory, render the necessary neural pathways obstructed to achieve analgesia? Acetylcholine Brain Pathway

connect to pain be more specific • : includes major groups of cholinergic cells in the medial septal nucleus, the nucleus of the diagonal band, and the nucleus basalis • project to the hippocampus and amygdala • throughout the cerebral cortex: crucial for learning/memory • widespread loss of these cells is characteristic of Alzheimer’s disease

• cholinergic cells in pedalculopontine and laterodorsal tegmental nuclei project to the reticular formation and thalamus • believed to be involved in arousal and sleep-wake cycle

• acts as variety of postsynaptic targets in PNS • at the neuromuscular junction of striated muscles • in the visceral motor system Dopamine Brain Pathway

• about 1 million nerve cells in human brain contain dopamine (DA)

• found in several main groups • mesostriatal system (aka nigrostriatal pathway) • originates in the substantial nigra and nearby areas of the mesencephalon (midbrain) • ascends as part of medial forebrain bundle to innervate the • specifically the caudate nucleus and putamen • thought to play a role in motor control • damage to these neurons can cause resting tremors, paralysis, or Parkinson’s disease • mesolimbocortical pathway • originates in the midbrain as well: ventral tegmental area (VTA) • projects to limbic system • amygdala, nucleus accumbens, hippocampus and the cortex

• also believed to be involved in motivation, reward, and reinforcement Serotonin Brain Pathway

• relatively few • concentrated in of the midbrain and brainstem along the midline

• large areas of the brain are innervated by serotonergic fibers

• implicated in the control of… • sleep and wakefulness • mood • anxiety • many other functions Norepinephrine Brain Pathway

• aka noradrenaline (noradrenergic)

• neurons that release NE are located throughout the brainstem • mostly in the locus coeruleus

• output of noradrenergic locus coeruleus cells extends throughout the cerebrum • including cerebral cortex • thalamic nuclei

• projects prominently to the cerebellum, pons, and spinal cord

• modulate many behavioral/psychological processes • mood • overall arousal • attention • sexual behavior Common Neurological Disorders

Alzheimer’s: loss of neurons and synapses in cerebral cortex • degeneration of temporal and parietal lobes, parts of frontal cortex and cingulate gyrus and brainstem nuclei (locus coeruleus) • neurofibrillary tangles visible by microscopy

Multiple Sclerosis (MS): caused by lesions move up into neural transmission in the CNS and destruction of myelin instead of end sheaths of neurons MS - myelin (include diameter pic) • mostly effects white matter in optic create slide for myelination

nerve, brainstem, basal ganglia, andkeep this slide: under construction spinal cord list and hyperlink • white matter cary signals to in brain • PNS rarely involved

Parkinson’s: basal ganglia (in dopaminergic system) most effected and cell death in the substantia nigra • responsible for motor control • experience of hypokinesia Activity at the Synapse

• Chemical Receptors: the mechanism that released NTs bind to • NTs act as a key and the receptor acts as a lock

• the effect on the postsynaptic neuron is determined by the type of receptor that’s activated • NOT by the presynaptic neuron or the NT

Step 1: synthesis of neurotransmitters

Step 2: neurotransmitter release • calcium influx (initiation of NT release) • mobilization of synaptic vesicles • role of specialized proteins • vesicle docking, fusion, and exocytosis Step 3: neurotransmitter postsynaptic receptors • ionotropic receptors • metabotropic receptors

Step 4: inactivation of neurotransmitters • enzymatic degradation of NTs • enzyme inhibition • reuptake • transporter inhibition Main Advancements In Technology/Understanding

• understanding individual differences • genetically: CCK release and density • associated with sensitivity to acupuncture • psychologically

• brain regions associated with analgesia conflation:confirmed too many ideas that may be and explored by… unrelated • FMRI: functional magnetic resonance imaging • PET scan: positron emission tomography

• electrical acupuncture • in conjunction with NMDA or AMPA/KA receptor antagonists have a synergic antinociceptive action against inflammatory pain • in conjunction with glial function synergistically suppresses inflammatory pain