1 Signal transduction in nociceptors Nociceptor-specific Na+ - PDF document

Basic mechanisms of pain To understand the pharmacology of pain, you must know the anatomy and physiology of the system. PAIN - an unpleasant sensory and 1. Peripheral nociceptors emotional experience 2. Dorsal horn – major center for integration of afferent and efferent signaling associated with actual or 3. Ascending pathway potential tissue damage. 4. Descending pathway - has a dedicated neural pathway - individual and subjective - more than a symptom ` DIFFERENT KINDS OF PAIN: - Acute - Inflammatory - Neuropathic Amy MacDermott, PhD Department of Physiology and Cellular Biophysics and the Center for Neurobiology and Behavior. Fig from Brain Awareness – SFN 2003 Fig from Brain Awareness – SFN 2003 Different levels of pain processing Different levels of pain processing and different sites for sensitization. and different sites for sensitization. DRG DRG Kandel Schwartz Jessell Ch 24 Kandel Schwartz Jessell Ch 24 How are peripheral temperature and pain signals detected? DRG Different levels of pain processing and different sites for sensitization. Nociceptor Primary Afferent Terminal Dorsal Root Peripheral Nerve Ending DRG Spinal Cord Thermal Mechanical Chemical Kandel Schwartz Jessell Ch 24 1

Signal transduction in nociceptors Nociceptor-specific Na+ channels ASIC VR1/VRL-1 CMR1? ENaC/DEG Nav 1.8 and 1.9 are expressed exclusively in small diameter peripheral sensory neurons. Channel expression changes induced by nerve injury contribute to neuropathic pain. NA v1.8 NA v1.9 ASIC – acid sensing ion channel VR1 – vanilloid receptor 1 CMR1 – cold and menthol activated receptor 1 Degenerin family Modified from Julius and Dib-Hajj et al, 2002 Basbaum, 2001 Two populations of C and A δ fibers projecting to the superficial Afferent fiber conduction and pain dorsal horn Thermal nociceptors, A δ, C fibers , extreme heat and cold Mechanical nociceptors A δ and C There are multiple types of nociceptors: they can differ by sensitivity to growth factors, peptide expression, conduction velocity, sensory modality Polymodal nociceptors C Julius and Basbaum, 2001 Hunt and Mantyh, 2001 Molecular mechanisms associated with peripheral sensitization Different levels of pain processing and different sites for sensitization. DRG Julius and Basbaum, 2001 Kandel Schwartz Jessell Ch 24 2

Peripheral terminals of primary afferent nociceptors respond to The peripheral signal is carried to the spinal cord inflammatory mediators DRG Nociceptor Primary Afferent Terminal Dorsal Root Peripheral Nerve Ending Spinal Cord ATP, Ach and serotonin released from damaged endothelial cells and Thermal platelets Mechanical Chemical Histamine from mast cells Bradykinin from plasma kininogen Julius and Basbaum, 2001 Nociceptive inputs go to lamina I, II and V in the dorsal horn Nociceptors terminating in the superficial dorsal horn DH release glutamate and peptides to excite dorsal horn neurons. L5 L5 Adult mammalian spinal cord Adapted from Fields, 1987 Synapses between primary afferent C fibers and dorsal horn neurons Classes of neurotransmitter receptors D = dorsal horn neurons C = C fiber terminal - + OUT ++++++ ++++++ ++++++ +++ +++ ++ C fiber afferent stained -------- - -------- ------------ ------- α for substance P β γ IN G Protein coupled IONOTROPIC receptor Kandel, Schwartz Jessell Ch 24 3

Glutamate receptor families Synaptic transmission between nociceptors and dorsal horn neurons Na + , (Ca 2+ ?) Na + , Ca 2 GLU, GLU, + GLU, KA KA GLU NMDA OUT α β IN γ ∗ K + K + metabotropic NMDA AMPA Kainate receptors receptors receptors Glu receptors (NMDARs) Current-voltage relationship for synaptic currents mediated by AMPA and NMDA receptors The spinal cord dorsal horn has a heterogeneous cell population including: -projection neurons -excitatory interneurons -inhibitory interneurons Kandel, Schwartz and Jessell, 2000 Dorsal horn neurons expressing receptor for substance P, the NK1 receptor. Different levels of pain processing and different sites for sensitization. Lamina I Lamina II DRG Lamina III Lamina I projection neuron Hunt and Mantyh, 2001 Kandel Schwartz Jessell Ch 24 4

Activation of neural plasticity in the spinal cord dorsal horn: fast EPSPs Thermal injury can sensitize nociceptors Kandel, Schwartz Jessell Ch 24 Woolf and Salter, 2000 Increased number of astrocytes in spinal cord in model of bone cancer Central sensitization Schwei et al, 1999 Increase in number of microglia following peripheral nerve Ascending nociceptive pathway- injury accompanies tactile allodynia anterolateral white matter to the thalamus DRG Tsuda et al, 2003 Kandel Schwartz Jessell Ch 24 5

The thermal-grill illusion of pain -burning pain with innocuous warm (40 o ) and cool (20 o ) bars. Ascending Pain Demonstrates central pathways: inhibition of a polymodal C nociceptive sensory -traditional channel by innocuous -lamina I thermosensory activity. Craig NRN, 2002 Descending pathway that regulates nociceptive signaling in dorsal horn Activation of the interoceptive or homeostatic cortex (the dorsal posterior insular cortex) by various modalities •Descending Pathway –Periaqueductal grey (PAG) –Dorsolateral pontomesencephalic tegmentum (DLMT) –Rostral ventromedial medulla (RVM) –Nucleus raphe magnus –Reticular formation –Dorsal horn Kandel, Schwartz, Jessell Ch 24 Wall and Melzack, Ch 11 Craig 2002 Opioid receptors – 3 gene families Opioid receptor action µ opioid receptor – activated by morphine, β endorphin and enkephalins κ opioid receptor activated by dynorphin δ opioid receptors activated by enkephalins and β endorphin Bonica’s Management of Pain Ch 4 Bonica’s Management of Pain Ch 4 6

Local circuit interneurons Opioids are important regulators of nociceptive signaling Kandel Schwartz Jessell Ch 24 Kandel, Schwartz Jessell Ch 24 DRG Nociceptor Primary Afferent Terminal Dorsal Root Peripheral Nerve Ending Spinal Cord Summary: - There are multiple types of nociceptors: they can differ by sensitivity to growth factors, peptide expression, conduction velocity, sensory modality - All nociceptors release glutamate thus glutamate receptors are potential targets for pain management - Sensitization occurs peripherally and centrally - Dorsal horn neurons project to multiple higher levels in the brain, notably the parabrachial nucleus, the thalamus and the insular cortex and receive descending input, directly or indirectly, from all of those same areas - There are good targets for pain management on peripheral and central terminals of nociceptors as well as through regulation of inhibition in the dorsal horn 7