Re: PAG pain modulation 과 관련된 그림과 논문

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This complex nociceptive system is balanced by an equally complex antinociceptive system (Figure 2). Pain signals arriving from peripheral tissues stimulate the release of endorphins in the periaqueductal gray matter of the brain and enkephalins in the nucleus raphe magnus of the brainstem. The endorphins inhibit propagation of the pain signal by binding to µ-opioid receptors on the presynaptic terminals of nociceptors and the postsynaptic surfaces of dorsal horn neurons. The enkephalins bind to delta-opioid receptors on inhibitory interneurons in the substantia gelatinosa of the dorsal horn, causing release of gamma-aminobutyric acid (GABA) and other chemicals that dampen pain signals in the spinal cord.

Spinal interneurons release dynorphin, which activates kappa-opioid receptors and leads to closure of N-type calcium channels in the spinal cord cells that normally relay the pain signal to the brain. Following the release of enkephalins, spinal cord cells release other small molecules, including norepinephrine, oxytocin, and relaxin, that also inhibit pain signal transmission.

Enkephalin is particularly notable in that it binds to delta-opioid receptors that are selectively exposed on nociceptive nerves when they are actively transmitting a pain signal. These receptors are usually localized on presynaptic vesicles containing neurotransmitters. After the neurotransmitters are released, the receptors are incorporated into the presynaptic cell membrane. Active nociceptors thus become more sensitive than inactive nociceptors to both endogenous and exogenous opiates, which may explain how certain opioid analgesics relieve ongoing pain without impairing the ability to sense the pain caused by new injuries.

This natural pain-relieving system may be as important to normal functioning as the pain-signaling system. Because of it, minor injuries such as a cut finger or stubbed toe make us upset and dysfunctional for only a few minutes--not for days, as might be the case if the pain persisted until the injury completely healed. We are thus able to cope with life's daily pains without constantly suffering. But just as disorders of the pain-sensing system can give rise to illness and dysfunction, so can disorders of the pain-relieving system. Fibromyalgia, a condition that many clinicians consider to be factitious, may be one example of a debilitating disease caused by antinociceptive dysfunction. Chronic pain is not just a prolonged version of acute pain. As pain signals are repeatedly generated, neural pathways undergo physiochemical changes that make them hypersensitive to the pain signals and resistant to antinociceptive input. In a very real sense, the signals can become embedded in the spinal cord, like a painful memory. The analogy to memory is especially fitting since the generation of hypersensitivity in the spinal cord and memory in the brain may share common chemical pathways.

Activation of NMDA Receptors. The main neurotransmitter used by nociceptors synapsing with the dorsal horn of the spinal cord is glutamate, a versatile molecule that can bind to several different classes of receptors. Those most involved in the sensation of acute pain, AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic-acid) receptors, are always exposed on afferent nerve terminals. In contrast, those most involved in the sensation of chronic pain, NMDA (N-methyl-D-aspartate) receptors, are not functional unless there has been a persistent or large-scale release of glutamate. Repeated activation of AMPA receptors dislodges magnesium ions that act like stoppers in transmembrane sodium and calcium channels of the NMDA receptor complex. The conformational change in the neuronal membrane that makes these receptors susceptible to stimulation is the first step in central hypersensitization (Figure 3) and marks the transition from acute to chronic pain.

The Role of the Periaqueductal Gray in the Modulation of Pa.pdf

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LECTURE OUTLINE (CHAPTER 10)

LECTURE OBJECTIVES

1. Establish how sensory neurons interpret specific stimuli.
2. How is this sensory information processed in the PNS and CNS?
3. Discuss some of the conditions that result from malfunction of sensory input.

LECTURE OUTLINE

I. INTRODUCTION

  A. Primary functions of the Peripheral Nervous System (PNS)
     1. Sensory input
     2. Motor output
  B. Types of sensory neurons
  C. General characteristics of sensory neurons
     1. Graded response results in an action potential
     2. Receptor and Generator Potentials    
          a. Dendritic action potentials
     3. Tonic verses Phasic firing
     4. Lateral inhibition 
     5. Receptive fields 




  D. Introduction to sensory pathways to brain
     1. Sensory systems often map to specific cortical locations 

II. PAIN

  A. Nociceptor structure and function
     1. Similarities between nociceptors and thermoreceptors
  B. Fast and slow pain
     1. Myelinated and unmyelinated fibers
  C. Pain pathway projections in the CNS
  D. The brain's analgesic system
     1. Periaqueductal gray, raphe, and pain suppression
          a. Role of endogenous opioids, such as enkephalin
     2. Referred pain

III. TASTE AND SMELL 





  A. How are taste and smell related?
     1. Summary of functional similarities 
     2. Functional differences
  B. Taste
     1. How a chemical stimulus activates its taste receptor?
          a. Signal transduction for taste
              1) Second messengers (e.g., Ca++) have a central role
     2. Integration of taste 
  C. Olfaction
     1. Functional organization of the olfactory epithelium
     2. Odor is a "lock and key" association 
     3. Integration of olfaction 





IV. HEARING AND BALANCE

  A. Introduction to the ear
     1. Relationship between hearing and balance
     2. Ear is divided into outer, middle, and inner ear
  B. How does the ear hear?
     1. Role of hair cells in basilar membrane
           a. Importance of K+ influx 
     2. Hearing frequency and loudness
           a. A tonotopic map exists in the auditory cortex 
     3. Summary (Animation on how we hear)
  C. Balance and sensing movement and position
     1. Roles of semicircular canals, cupula, kinocilium
     2. Motion of the head and body    
     3.  Position of the head
          a. Role of ototliths in the utricle and saccule

V. VISION 





  A. Structure/Function of the eye
     1. Lens
          a. Refraction and accomodation by the lens
          b. Nearsightedness and farsightedness
     2. Iris 
     3. Retina
          a. Structure and function of rods and cones
               1) color vision
          b. Fovea is packed with cones
               1) Dysfunction: Macular degeneration
  B. Neuronal organization and integration in retina
          a. Rods and cones, bipolar, ganglion cells, etc.
          b. Function of each
     1. Phototransduction: Light activates rhodopsin (Animation)
          a. Signal transduction mechanism 
          b. Hyperpolarization of photoreceptor
          c. Light disinhibits bipolar neurons
          d. Ganglion cell fires an action potential
     2. Receptive fields of ganglion cells (Animation on visual processing) 
     3. Integration beyond the retina 




          a. Projection to lateral geniculate nucleus (LGN) and visual cortex
     
Review of sensory input and motor output 

Reading Assignment. Please read Chapter 11 and the first part of Chapter 12 for the next lecture. I will start to lecture on muscle physiology next Thursday.

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STUDY QUESTIONS ON SENSORY PHYSIOLOGY (CHAPTER 10)

BASIC FACTS AND TERMS

1. Compare the slow and fast pain pathways with respect to 1) characteristics of the sensory neurons (type of fiber, etc.), 2) the ascending pathways to the brain, and 3) analgesic modulation of the pain pathways by the CNS.

2. You place the point of a pencil on the back of your hand. Trace the path that the sensory input takes from your hand to the cerebral cortex. In correct order list all of the structures that the signal passes through. List all of the synapses that occur en route.
3. What is referred pain? Explain the neuronal basis for referred pain.
4. Define and give the physiological significance (how or why it is important) for the following terms:
   • Organ of Corti
     
   • Cupula
     
   • Cochlea
     
   • Otoliths
     
   • Olfactory glomeruli
     
   • Semicircular canals
     
   • Oval and Round windows
     
   • Periaqueductal gray (PAG)
     
   • Basilar membrane of the cochlea
     
   • Phasic receptor firing
     
   • Tonic receptor firing
     
   • Receptive field (of a ganglion cell)
5. List six neuronal cell types which make up the retina. Where is each located? How does each function?
6. Using a flow chart format, outline the correct order of cellular events associated with light transduction (=signal transduction pathway) in a rod.
7. What is the optical basis for nearsightedness (myopia) and farsightedness (hyperopia)? How do glasses adjust these conditions? (See Fig. 10-33)?

   
   CONCEPTS

8. What roles do the bones of the middle ear play in hearing? --roles of the oval and round windows? How does the cochlea sense differences in the 1) frequency and 2) loudness of a sound? Be sure to look at this animation on how the ear works, especially how sound activates the hair cells in the Organ of Corti. You are responsible for knowing the information presented in this animation.
9. In what ways are receptor potentials similar to Excitatory Post-synaptic Potentials (EPSPs)? Explain.
10. What is the receptive field of a ganglion cell? What are On-center Cells and Off-center Cells, and how do they function in vision? (see Text.) See this very good animation on how these cells work. You are responsible for knowning the information presented in this animation.
11. Diagram the visual paths from light input (rods and cones) to the primary visual cortex. What happens to this visual input at each step? How is light information coded at each step? See this animation for more details.
12. You are looking at a image that is far away. Where and how is the image altered as it passes through the eye to the retina? What change occurs in the eye that let you focus on a very close image (Read about accomodation in Silverthorn)? What is the default state for the lens?
13. When you first enter a dark room you can not see well, but with time your vision becomes better. What is the physiological basis for light adaptation? See Silverthorn.
14. What is the physiological basis for the following conditions?
    • night blindness
      
    • color blindness
15. Transduction of a stimulus usually causes depolarization of a sensory receptor. What is the cellular basis for depolarization of a sensory receptor? One exception to this rule is the photoreceptor which is hyperpolarized in the presence of light. Explain how this hyperpolarization is eventually realized as an action potential leaving the retina (See Fig. 10-39).
16. Explain pre-synaptic inhibition. Give an example and explain how it works.
17. How does the "lock and key" relationship between odorants and sensory receptors in the olfactory epithelium explain the multitude of complex smells that we can sense? Explain.
18. What are the cellular mechanisms for transduction of taste stimuli (salt, sweet, bitter, and sour)? You do not have to memorize these mechanisms, but look for generalizations, such as 1) how Ca++ is involved in signal transduction and neurotransmitter release, 2) how membrane depolarization is accomplished (Note that there is more than one way), and 3) how these mechanisms compare with what was covered in Figures 6-11, 6-12, and 6-13.
19. How is the internal structure of a rod and cone related to its function? Then, contrast rods and cones with respect to: 1) distribution in the retina, 2) sensitivity to light, 3) adaptation to light, and 4) visual acuity. At what point on the retina is vision the sharpest? Explain why this is case.
20. What is the neuronal basis for our ability to perceive subtle differences in the color spectrum?
21. How are mechanoreceptors involved in 1) hearing and 2) balance/head position? Draw each of these receptors. How are they alike in structure and function?
22. Which part of the cerebral cortex integrates 1) visual input, 2) auditory input, 3) gustatory input, 4) olfactory input, 5) somatosensory input, and 6) speech production and speech understanding. Which of these cortical areas have "point to point maps" for sensory input? Why have such "maps" in the cerebral cortex? Which sensory system apparently lacks a "point to point" map?
23. Afferent neurons often modulate their firing pattern to code specific sensory informaton. Give two different examples of how the nervous system encodes information about the intensity of a sensory input. What type of information does tonic firing convey? --phasic firing? Describe sensory adaptation and explain how it is used as a method of information coding. Describe lateral inhibition and explain how it is used as a method of information coding.
24. How does the vestibular apparatus sense 1) initiation of movement in a forward or backward direction and 2) turning the head?

    
    REASONING AND PROBLEM SOLVING

25. Pain results from tissue destruction. What chemical stimuli at the tissue level excite pain receptors? Aspirin is an analgesic. Given your knowledge of how the pain pathways work, give three different avenues by which aspirin might inhibit pain. Click here for the correct answer.
26. Ganglion cells consist of either ON-CENTER CELLS (=firing increases) or OFF-CENTER CELLS (=firing decreases) when white light appears in the "center" of the receptive field. When white light appears in the "surround area" (rather that center) of the receptive field, the opposite response occurs for both the ON (=decreases) and OFF cells (=increases). Can you expand on this general principle to explain how color-senstive ganglion cells might code for color vision?
27. A person training for a marathon is often said to be "addicted" to running. Further, not running often leads to "withdrawal-like" symptoms. Given your knowledge of how endogenous opioids (e.g., enkephalin) act in the CNS, what might be happening interally that could explain these symptoms?
28. The endolymph, which surrounds both the the inner hair cells in the inner ear and the cupula in the semicircular canals, is rich in K+, rather than Na+. This difference in ionic concentration is unique to these fluids. Given your general understanding of how ion flux leads to depolarization, how might K+ current play a role in depolarization of the inner hair cells and the cupula?

Descending inhibitory system

 

 

Descending control of persistent pain: inhibitory or facilitatory?

References and further reading may be available for this article. To view references and further reading you must purchase this article.

Horacio Vanegas^{a, b, ,} and Hans-Georg Schaible^b

^aInstituto Venezolano de Investigaciones Cientificas (IVIC), Apartado 21827, Caracas 1020A, Venezuela

^bInstitut fuer Physiologie, Friedrich-Schiller-Universitaet, Teichgraben 8, 07740 Jena, Germany

Accepted 6 July 2004. 

Available online 14 August 2004.

Abstract

The periaqueductal gray matter (PAG) and the nucleus raphe magnus and adjacent structures of the rostral ventromedial medulla (RVM), with their projections to the spinal dorsal horn, constitute the “efferent channel” of a pain-control system that “descends” from the brain onto the spinal cord. Considerable evidence has recently emerged regarding participation of this system in persistent pain conditions such as inflammation and neuropathy. Herein, this evidence is reviewed and organized to support the idea that persistent nociception simultaneously triggers descending facilitation and inhibition. In models of inflammation, descending inhibition predominates over facilitation in pain circuits with input from the inflamed tissue, and thus attenuates primary hyperalgesia, while descending facilitation predominates over inhibition in pain circuits with input from neighboring tissues, and thus facilitates secondary hyperalgesia. Both descending facilitation and inhibition mainly stem from RVM. The formalin-induced primary hyperalgesia, although considered a model for inflammation, is mainly facilitated from RVM. Also, formalin-induced secondary hyperalgesia is facilitated by RVM. Again, formalin triggers a concomitant but concealed descending inhibition. The (primary) hyperalgesia and allodynia of the neuropathic syndrome are also facilitated from RVM. Simultaneously, there is an inhibition of secondary neuronal pools that is partly supported from the PAG. Because in all these models of peripheral damage descending facilitation and inhibition are triggered simultaneously, it will be important to elucidate why inhibition predominates in some neuronal pools and facilitation in others. Therapies that enhance descending inhibition and/or attenuate descending facilitation are furthermore an important target for research in the future.

Keywords: Chronic pain; Formalin; Hyperalgesia; Inflammation; Neuropathy; Pain modulation