Receptors and Neurotransmitters: It Sounds Greek to Me Cathy Carlson, PhD, RN Northern Illinois University Agenda We will be going through this lecture on basic pain physiology using analogies, mnemonics, cartoons, rhymes, songs, games, and visualizations to: learn and learn to teach pain physiology What We Know About Pain 1
Anatomy of a Neuron Structural Classes of Neurons Unipolar Sensory Neurons and Ganglia 2
Pain & Sensory Receptors Primary Afferent Sensory Nerve Fibers A-alpha (Aα) Carry information related to proprioception (muscle sense) A-beta (A-β) Carry information related to touch A-delta(A-δ) Carry information related to pain and temperature C-nerve fibers Carry information related to pain, temperature, and itch 3
Neural Steps in the Processing of Pain Signals 1. Transduction - noxious stimuli are converted to electrical signals in sensory nerve endings. 2. Transmission - neural events which relay the information from the periphery to the cortex. 3. Modulation - the nervous system can selectively inhibit the transmission of pain signals. 4. Perception - subjective interpretation by the cortex of the noxious stimulus. a. Sensory component (intensity, location) b. Affective component (psychological) Transduction Transduction Begins in periphery All cellular damage caused by thermal, mechanical, or chemical stimuli result in the release of pain producing excitatory mediators Mediators surround the pain fibers in the extracellular fluid, spreading the pain message through excitation (depolarization) of the free nerve endings (nociceptors) of the pain fibers Also causes the inflammatory response This is called nociception Nocire means to suffer 4
Peripheral Excitatory Mediators Substance Receptor Mechanism Substance P (SP) Prostaglandin (PG) Bradykinin NK 1 neuronal excitability, edema? Sensitize nociceptors, inflammation, edema B 2 (normal) B 1 (inflammation) Sensitize nociceptors PG production Histamine H 1 C-fiber activation, edema, vasodilation Serotonin 5-HT 3 C-fiber activation, release SP Norepinephrine (NE) 1 Sensitize nociceptors Activate nociceptors Threshold Threshold 5
Depolarization Sodium/potassium pump polarizes neuron At resting state: K + intracellular Na ++ Extracellular More negative intracellular Stimulus begins wave of depolarization as Na ++ ion channels open and Na ++ rushes in Wave of repolarization follows close behind Opening of the Ion Channels Touch-pressure: Mechanical tension opens ion channels Rapidly adapting mechanoreceptors: vibration, touch, mov ement Slowly adapting mechanoreceptors: pressure Sense of posture and movement: Muscle stretch opens ion channels Muscle spindle stretch receptor: Responsible for the senses of posture and kinesthesia (sense of movement at a joint) Sense organs of balance: vision, vestibular organs, muscle spindles Temperature: Heat and cold Changes in temperature opens ion channels Pain: Tissue damage release chemical mediators that open ion channels Transmission 6
Transmission The transmission process occurs in three stages The pain impulse is transmitted: 1. From the site of transduction along the peripheral afferent neuron (first order neuron) to the dorsal horn in the spinal cord 2. From the spinal cord to the brain stem (second order neuron) 3. Through connections between the thalamus, cortex and higher levels of the brain (third order neuron) Transmission Characteristics and Functions of C fibers and A-δ Fibers 7
A δ and C Fiber Pain C fiber A fiber First pain Second pain Pain intensity Time Transmission C fibers and A-δ fibers terminate in the dorsal horn of the spinal cord A synapse exists A synapse contains three elements: 1. Presynaptic neuron a. Presynaptic terminal 2. Synaptic cleft 3. Postsynaptic neuron a. Receptive membrane For the action potential to be transmitted across the synaptic cleft to the postsynaptic neuron, excitatory neurotransmitters are released, which bind to specific receptors on the postsynaptic neuron Release and Reuptake of Neurotransmitters 8
Major Excitatory Neurotransmitters of Pain in Spinal Cord Synapse in the Dorsal Horn of Spinal Cord Central Nervous System Ascending Pathways Spinothalamic Tract Two subdivisions: Neospinothalamic tract (lateral spinothalamic tract) Acute pain Paleospinothalamic Tract (anterior spinothalamic tract) Dull/burning pain 9
Second Order Neurons in Spinal Cord Types Wide Dynamic range Receive impulses from A-beta, A-delta, & C Nociceptive specific Receive impulses from A-delta & C Interneurons May be inhibitory or excitatory Second Order Cells in the Spinal Dorsal Horn A A C Polymodal A C Polymodal Wide Dynamic Range (WDR) Dorsal Horn Lamina V + - Wide Dynamic Range Neuron To Brain To Brain Dorsal Horn Lamina I, V Nociceptive Specific Neuron Nociception Pathways 10
Perception Perception Point at which person is aware of pain Fast pain stimuli are transmitted up spinal cord to via the neospinothalamic tract with some fibers to the thalamus and the majority of fibers to the somatosensory cortex Identifies location & intensity of pain Perception Slow pain stimuli are transmitted up spinal cord to via the palespinothalamic tract to the midbrain and thalamus limbic system Limbic system-controls emotion, anxiety, & emotional reaction to pain Responses to pain can be physiological and behavioral 11
Modulation Modulation of Pain Involves changing or inhibiting transmission of pain impulses in the spinal cord. Multiple, complex pathways involved in the modulation of pain Increases the transmission of pain impulses (excitatory) or decreases transmission (inhibition) Modulation of Pain at the Spinal Cord Level Gate Control Theory of Pain Pain impulses can be regulated or even blocked by gating mechanism along CNS Theory suggests that pain impulses pass when gate is open and blocked when gate is closed Closing the gate is basis for pain relief interventions 12
Gate Control Theory of Pain, Cont. Involves the addition of mechanoreceptors (A-β neurons), which releases inhibiting neurotransmitter (Serotonin) If dominant input is from A-β fibers, gating mechanism will close, pain reduced, due to release of Serotonin If dominant input from A-δ fiber, gate will be open and pain perceived Release of endorphins also close gate Descending Modulatory Pain Pathways (DMPP) Transmit impulses from the brain (corticospinal tract in the cortex) to the spinal cord (lamina) Periaquaductal Gray Area (PGA) releases enkephalins Nucleus Raphe Magnus (NRM) releases serotonin The release of these neurotransmitters inhibit ascending neurons Stimulation of the PGA in the midbrain & NRM in the pons & medulla causes analgesia. Descending Modulatory Pain Pathways (DMPP) Afferent stimulation of periaqueductal gray (PAG) area stimulates efferent neurons Periaquaductal Gray Area (PGA) releases enkephalins and secretes serotonin Rostral pons secretes norepinephrine Nucleus Raphe Magnus (NRM) releases serotonin Efferent neurons synapse in medulla Impulse travels to dorsal horn to block afferent sensory fibers 13
Inhibitory Neurotransmitters of Pain Inhibitory neurotransmitters involved with the modulation of pain include: 1. Endogenous opioids Endorphins, enkephalins, dynorphins, and endormorphins 2. Gamma-aminobutyric acid (GABA) Widespread in brain and spinal cord Amygdala Inhibitory GABA receptors on WDR neurons inhibit excitatory neurotransmitter release 3. Neurotensin Highest levels in hypothalamus, amygdala, and nucleus accumbens Causes analgesia and is also involved in regulation of dopamine pathways 4. Acetylcholine Increased release of spinal acetylcholine is associated with an elevated pain threshold Inhibitory Neurotransmitters of Pain 5. Oxytocin Released by receptors in the PGA Believed to play an antinociceptive role Binds to μ and κ opioid receptors 6. Norepinephrine PGA Different effects in different parts of body In descending pathways causes inhibition of transmitter release from peripheral afferent neuron Cingulate Cortex 7. Serotonin (5-HT) Inhibits pain in pons and medulla Transmitter in descending inhibitory pathways Inhibits substance P transmission in dorsal horn (mechanism uncertain) 8. Dopamine Inhibits processing of pain in multiple levels of the central nervous system including the spinal cord, periaqueductal gray (PAG), thalamus, basal ganglia, insular cortex, and cingulate cortex Endogenous Opioids Endorphin receptors are found in periphery, ascending, and descending pathways 4 Types 1. Endorphins Located in hypothalamus and pituitary Bind to both μ and δ receptors with comparable affinity Produce a sense of exhilaration, or high 2. Enkephalins Located in neurons of brain, spinal cord Bind with the δ receptor Found concentrated in the hypothalamus, the PAG matter, the nucleus raphe magnus of the medulla, and the dorsal horns of the spine 3. Dynorphins Bind with the κ receptor Located in the hypothalamus, the brainstem, PAG, rostral ventromedial medulla (PAG-RVM) system, and the spine Most powerful 4. Endomorphins Located in the brain and the spinal cord and PNS Show the highest affinity and selectivity for the μ receptor Thought to assist in adaptation to pain and stress and enhancement of reward perceptions Release of endorphins can raise an individual s pain threshold Release is increased by Stress, excessive physical exertion, acupuncture, intercourse, and other factors 14
Important opioid receptors: mu ( ), kappa ( ), delta ( ) Activation of opioid receptors by endogenous opioids inhibits the release of excitatory neurotransmitters such as substance P in the brain, spinal cord, and peripheral nervous system Opioid Receptors Opioid Receptors Questions? 15