Ch.1 Anatomy and Physiology of Somatosensory and Pain Processing 마취통증의학과 R3 임태완

1. Ch.1 Anatomy and Physiology of Somatosensory and Pain Processing 마취통증의학과 R3 임태완 Definition of pain (The International Association for the Study of Pain) - an unplesant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage SOMATOSENSATION, NOCICEPTION, AND PAIN Somatosensation– physiologic process by which neural substrates are activated by physical stimuli resulting in the perception of what We describe as touch, pressure, pain,etc Nociception - physiologic process of activation of neural pathways by stimuli that are potentially or actually damaging to tissue Pain– in contrast to nociception, is a conscious experience, while the stimulus-induced activation of afferent neural pathways and other factors may play

2. Sequence of events by which a stimulus is perceived (1) Transduction– occurs in the pph. Terminals of primary afferent neurons where different forms of energy, e.g., mechanical, heat, cold, are converted to electrical energy(action potential) (2) Transmission– electrical activity induced by a stimulus is conducted through the nervous system (3) Modulation – neural activity may be altered along the pain transmission pathway e.g. dorsal horn (4) Perception– neural activity in the somatosensory transmission pathway results in a subjective sensation of pain d/t concerted activation of primary and secondary somatosensory and limbic cortex

3. PERIPHERAL MECHANISMS Primary afferent fibers –part of the pph. NS with their cell bodies located in the dorsal root ganglia classification : based on conduction velocity cutaneous stimuli by which they are activated primary afferent fibers in skin based on conduction velocity A-beta– fastest, large diameter myelinated, not transmit pain transmit light touch, pressure, hair movement C– prolonged burning sensation slower-onset second burnig pain A-delta– sharp, intense, tingling sensation rapid-onset first sensation of pricking pain

4. Nociceptive afferents are further subclassified based on (1) molecules expressed on their cell surface (e.g. receptors, glycoconjugates) (2) molecules they store and release (e.g. peptides) (3) enzymes they contain

5. SPINAL MECHANISMS The first synapse in somatosensory processing from the body surface dorsal column nu. at the spinal cord-brainstem junction spinal dorsal horn Somatosensory processing from the face Processed in the spinal trigeminal nu. or in the chief sensory nu. of the trigeminal n. located in the midpons region ot the brainstem Under normal circumstances, dorsal column nu. And the chief sensory nu. – input from A-beta spinal dorsal horn and spinal trigeminal nu. – input from A-delta, C Rexed laminae nociceptive primary afferent fibers terminate in the spinal dorsal horn in a highly ordered way I, II – C I, III, IV, V – A-delta III, IV, V – A-beta terminate

6. second-order nociceptive spinal & spinal trigeminal projection neuron : WDR(wide dynamic range) neurons NS(nociceptive specific) neurons WDR – lamina III , IV, V receive input from low-threshold A-beta & A-delta, C activated by both innocuous and noxious stimuli NS – lamina I, outer II respond only to noxious stimuli lower rate of spontaneous activity than WDR slower than WDR

7. SPINAL MODULATION Gate Control Theory by Melzack & Wall : concept of modulation of noxious inputs at spinal levels input along low-threshold(A-beta) fibers inhibit the responses of WDR cells to nociceptive input suggested theory for explanation for the efficacy of transcutaneous electrical stimulation for pain for pain relief → subsequent studies have identified intrinsic spinal neurons that release several different NT in the spinal cord that play a role in the modulation of nociceptive impulses modulation can result in augmented or inhibited output from spinal cord pain signaling neuron and determine what messages are delivered to the higher levels the CNS.

8. Special types of spinal modulation central sensitization - the capacity for transmission in the nociceptive system is changed or shows neuronal plasticity The result of neuronal plasticity is that following a noxious stimulus of sufficient intensity and duration, such as a surgical incision, coding of pain-signaling neurons for a given stimulus may be increased. windup– example of central plasticity repeated stimulation of C fibers results in progressive increase in the number of discharges expansion of receptive field size and an increase in spontaneous discharge rate * WDR : sensitized more readily than NS

9. SUPRASPINAL MECHANISMS struncture : brainstem, diencephalic, & cortical sites two set of somatosensory inputs to the brain stem and diencephalon 1. many axons and axon collaterals of the spinal projection neurons that ascend in the anterolateral spinal quadrant depart this ascending tract to terminate in a number of nu. Of the brainstem and midbrain. target : brainstem autonomic regulatory sites - cardiovascular, respiratory function midbrain – ascending & descending modulation 2. Those primary afferent fibers that ascend in the dorsal columns of the spinal cord to form their first synapse at the dorsal column nu. input from the lower extremities – synapse most medially in the nu. Gracilis upper extremities – synapse laterally in the nu. Cuneatus face – processed in the chief sensory nu. Of the V n. Located at the site of origin of V n. in the midpons of the brainstem

10. The axons of the second-order cells in the dorsal column nu. - cross the midline and form the medial lemnicus on the contralat. side of the brainstem These fibers then ascend through the brainstem and midbrain terminate ventral post. Lat.(VPL) nu.(from the body) ventral post. Med.(VPM) nu.(from the face) of thalamus Somatosensory inputs to the cortex - third-order projections from thalamic somatosensory relay neurons of VPL and VPM as well as third order neurons projecting from brainstem and midbrain relay neurons

12. Ch 2. Neurochemistry of Somatosensory and Pain processing NEUROCHEMISTRY OF PAIN TRANSDUCTION tissue injury → local release of numerous chemicals → pain transduction by activating nociceptors or facilitate pain transduction by increasing the excitability of nociceptors Inflammatory Soup Bradykinin – role in inflammatory pain, hyperalgesia acute pain by activation of nociceptors heat hyperalgesia Low pH – found in inflammed tissues pain , hyperalgesia , selectively activation and sensitization of nociceptors to mechanical stimuli

13. Serotonin– release from PLT pain when applied to a human blister base by activation of nociceptors bradykinin-induced pain and nociceptor activation Histamine – release from mast cell by substance P vasodilation, edema itching(by exogenous histamine) Eicosanoids – PGs, LTs, TXs PGs : induced by inflammation reduce the activation threshold of tetrodotoxin-resistant Na currents in nociceptors increase intracellular cAMP increase the excitability of sensory neurons LTs : hyperalgesia, sensitization to mechanical stimuli AMP, ADP, ATP– released or leaked into extracelluar space with tissue injury and inflammation pain, hyperalgesia

14. Cytokines– IL-1beta, 6, TNF alpha regulate inflammatory cell response promote pain signaling Excitatory A.A.– present on dorsal root ganglia cell & presynaptic terminals of primary afferents role in modulation NGF(nerve growth factor)– inflammatory pain stimulate mast cells to release histamine and serotonin → heat hyperalgesia sensitizes nociceptors and may alter the distribution of A delta

16. Peripheral Anti-hyperalgesic mechanisms Opioids– may produce analgesia in inflamed tissues increased amounts are found in inflamed tissues Acetylcholine - modulation on nociception on pph. cholinergic R nicotine : weak excitatory effect on C nociceptor mild sensitization to heat no alteration in mechanical responsiveness muscarine : desensitizes C nociceptor to mechanical and heat stimuli GABA –modulation of pain transmission similar to ACh

17. Peripheral Second Messenger Pathways Inflammation is associated with the release of a host of chemical mediators.While some of chemical mediators may directly activate nociceptors, most of the inflammatory mediators lead to changes in the sensory neuron rather than directly activating it. e.g. phosphorylation of transducer molecules and voltage-gated ion channel in the pph. Terminals of nociceptors longer-lasting transcription-dependent changes in effector genes PKA and PKC induce a short-term sensitization of nociceptors to heat by modulating the activity of tetrodotoxin-resistant sodium currents.

18. NEUROCHEMISTRY OF PAIN TRANSMISSION Anterolateral and dorsal column medial lemniscal pathway Excitatory NT, Inhibitory NT, neuropeptide are found in sensory afferent terminals, local circuit terminals, descending modulatory circuit terminals Excitatory Neurotransmitters Glutamate, Aspartate Receptor –NMDA receptor non-NMDA receptor : kainate, AMPA, metabotropic NMDA– recruited only by intense and/or prolonged stimuli relieved by prolonged depol. linked to Ca ionophore that when activated results in many long term changes in excitability of sensory neuron(sensitization) kainate, AMPA– linked to Na Ch. mediate majority of the fast synaptic afferent signaling Metabotropic– a family of G-prot.-linked sites modulation of multiple cellular kinases, receptor, ion Ch., transcription factors

20. Inhibitory Neurotransmitters Glycine, GABA Glycine– esp., spinal level receptor site : Cl-linked strychnine-sensitive inhibitory receptor strychnine-insensitive modulatory site on the NMDA glutamate receptor complex GABA–higher level than spinal level found in local circuit neurons of spinal laminae I, II, III receptor type : GABAA – linked to Cl Ch. modulated by barbiturate, BDZ, alcohol agonist : muscimol antagonist : gabazine GABAB - asso with K ionophore and G prot.complex agonist : baclofen antagonist : phaclofen GABAC – asso with K ionophore agonist : CACA no modulation of somatosensory information Alterations in the function of the inhibitory NT : important with the induction of hyperalgesia and following the development of neuropathic pain

21. Norepinephrine – inhibitory NT in descending brainstem projections to the dorsal horn function of NE after injury to the nervous systems might become reversed from an inhibitory role into promoting on going chronic pain state Serotonin – major inhibitory NT in pathways descending to the spinal dorsal horn from the midbrain raphe nu. some receptor subtypes promote nociception, others are inhibitory Adenosine – inhibitory NT at spinal level receptor type : A1, A2 G-prot.-mediated alterations of cAMP Acetylcholine – mediates antinociception at the level of the spinal dorsal horn antinociceptive effects by muscarinic not by nicotinic receptor subtypes

22. Neuropeptides : more gradual onset and more prolonged duration of action than NT excitatory – substance P, neurokinin A esp. concentrated in primary afferent fiber at the spinal level, only released after noxious stimuli that are sufficient to produce sustained discharges in C signal as trans-synaptic transmitter not confined to a site of aciton on the immediate post- synaptic memb., instead tend to spread throughout the dorsal horn inhibitory – at the spinal level, somatostatin, enkephalins, dynorphin in intrinsic neurons of the dorsal horn and in the fibers descending to the dorsal horn from various brainstem nu. at the thalamic level, include endorphins

23. Central Signal Propagation and Second Messenger Systems : propagation of bioelectric signals in the CNS is dependent on the movement of various ions and the activity of cellular enzymes and metabolites. Ion channel involved in pain signal propagation in the CNS : Na, Ca, K, Cl Channel Na Ch. - depol. Of n. memb. key to propagation of neural impulse Ca Ch. - regulation of neuronal excitability release of NT with synaptic depol. Ca Ch. e.g. L, N, T, P type L, N type – antinociceptive effect

24. K Ch.- 2 nd main cation of neuronal action potential vol.gated Ch.: during repol., allows outward + current flow Blockade prolongs generation of action potential Continued application prevents repol. and ultimately fail to produce action potential inwardly rectifying Ch. : establish & regulate neuronal excitability Cl Ch. – inward movement of Cl current, hyperpolarize neuron ligand-gated Cl Ch.: GABA type A, glycine receptor common in dorsal horn neuron voltage-gated Cl Ch.: at spinal level Cl Ch. Activated cAMP : cystic fibrosis memb. regulator Second messenger systems in pain sensitivity At present, the role of these systems in pain management is indirect through the action of various drugs that interact with surface receptors Linked to G proteins.