Progress in Neurobiology 66 (2002) 355–474 Descending control of pain Mark J. Millan∗ Department of Psychopharmacology, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy/Seine, Paris, France Received 11 November 2001; accepted 7 February 2002 Abstract Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at ␣2-adrenoceptors (␣2-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain. © 2002 Published by Elsevier Science Ltd. Contents 1. General introduction: scope and aims of review .............................................. 359 2. Organisation of descending input to the DH.................................................. 360 2.1. Relationship of descending pathways to primary afferent fibres and intrinsic DH neurones ... 360 2.1.1. Neuronal circuitry in the DH ..................................................... 360 2.1.2. Multiple roles of transmitters in descending pathways: inhibition and facilitation ..... 360 2.2. Preferential modulation by descending pathways of nociceptive as compared to non-nociceptive information ........................................................................... 362 2.3. Role of volume transmission in the actions of descending pathways ....................... 364 2.4. Interactions of descending pathways with glial and immunocompetent cells ................ 364 2.5. Actions of descending pathways in spinal cord regions other than the DH .................. 365 2.5.1. Modulation of autonomic (sympathetic and parasympathetic) outflow ................ 365 2.5.2. Modulation of motor function .................................................... 365 Abbreviations: 5-HT, serotonin; ␣2-AR, ␣2-adrenoceptor; AC, adenylyl cyclase; ACh, acetylcholine; AMPA, ␣-amino-2,3-dihydro-5-methyl-3-oxo-4- isoxazolepropanoic acid; ATP, adenosine triphosphate; CB, cannabinoid; CCK, cholecystokinin; CGRP, calcitonin gene related peptide; DA, dopamine; DF, descending facilitation; DH, dorsal horn; DI, descending inhibition; DRG, dorsal root ganglion; DYN, dynorphin; ENK, enkephalin; ␤-EP, ␤-endorphin; EXIN, excitatory interneurone; GABA, ␥-amino-butyric acid; GAL, galanin; 5-HT, serotonin; I, imidazoline; IML, intermediolateral cell column; IN, interneurone; ININ, inhibitory interneurone; i.c.v., intracerebroventricular; i.t., intrathecal; MC, melanocortin; MIA, morphine-induced antinociception; NA, noradrenaline; NMDA, N-methyl-d-aspartate; NO, nitric oxide; NPFF, neuropeptideFF; NPVF, neuropeptideVF; NRM, nucleus raphe magnus; NT, neurotensin; NST, nocistatin; NTS, nucleus tractus solitarius; OFQ, orphaninFQ; ORL, opioid-receptor-like; OT, oxytocin; PAG, periaqueductal grey; PAF, primary afferent fibre; PBN, parabrachial nucleus; PLC, phospholipase C; PN, projection neurone; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus; RVM, rostroventromedial medulla; SP, substance P; SPA, stimulation-produced antinociception; VH, ventral horn; VP, vasopressin ∗ Tel.: +33-1-55-75-24-25; fax: +33-1-55-72-24-70. E-mail address: [email protected] (M.J. Millan). 0301-0082/02/$ – see front matter © 2002 Published by Elsevier Science Ltd. PII: S0301-0082(02)00009-6 356 M.J. Millan / Progress in Neurobiology 66 (2002) 355–474 3. Supraspinal origins of pathways descending to the DH ........................................ 366 3.1. Common sites of origin for mechanisms of descending inhibition and facilitation ........... 366 3.2. Supraspinal regions giving rise to pathways directly descending to the DH ................. 367 3.2.1. Hypothalamus................................................................... 367 3.2.2. Parabrachial nucleus ............................................................. 367 3.2.3. Nucleus tractus solitarius......................................................... 367 3.2.4. Rostroventromedial medulla ...................................................... 367 3.2.5. Dorsal reticular nucleus of the medulla............................................ 368 3.3. Role of the periaqueductal grey in the modulation of descending controls .................. 368 3.4. The cerebral cortex and descending controls ............................................. 369 4. Physiological significance and functional roles of descending controls .......................... 369 4.1. Interplay of descending inhibition and facilitation in the signalling of nociceptive information 369 4.2. Environmental stimuli adaptively engaging descending inhibition .......................... 370 4.3. Activation of multiple mechanisms of descending facilitation.............................. 370 4.4. Influence of chronic, pathological pain upon descending inhibition and facilitation .......... 371 4.5. Therapeutic manipulation of mechanisms of descending inhibition and facilitation .......... 372 4.6. Multiple neurotransmitters, multiple classes of receptor and descending controls ............ 372 5. Descending noradrenergic pathways and multiple adrenoceptors ............................... 372 5.1. Multiple classes of adrenoceptor ........................................................ 372 5.2. Supraspinal sources of noradrenergic input to the spinal cord.............................. 372 5.3. Modulation of the activity of descending noradrenergic pathways .......................... 373 5.4. Physiological roles of descending noradrenergic pathways ................................ 374 5.5. Influence of cerebral noradrenergic mechanisms upon other descending pathways ........... 374 5.6. Antinociceptive actions mediated by α2-adrenoceptors in the spinal cord ................... 374 5.7. Cardiovascular and motor actions mediated by α2-adrenoceptors in the spinal cord.......... 375 5.8. Mechanisms of α2-adrenoceptor-mediated antinociception in the DH....................... 376 5.8.1. Intracellular transduction ......................................................... 376 5.8.2. Interactions with other transmitters and mediators .................................. 376 5.9. Co-operative antinociceptive actions of α2-adrenoceptor agonists and other classes of analgesic agent ..................................................................... 377 5.9.1. Cholinergic agonists ............................................................ 377 5.9.2. Opioid agonists ................................................................ 377 5.9.3. GABAergic agonists ............................................................ 377 5.9.4. NMDA receptor antagonists ..................................................... 378 5.9.5. Local anesthetics ............................................................... 378 5.9.6. Serotonergic ligands ............................................................ 378 5.9.7. Adenosine agonists ............................................................. 378 5.9.8. Cyclooxygenase inhibitors....................................................... 378 5.9.9. Therapeutic significance......................................................... 378 5.10. Multiple classes of α2-adrenoceptor in the spinal modulation of nociceptive processing ..... 379 5.10.1. Imidazoline sites, agmatine and multiple classes of adrenoceptor .................. 379 5.10.1.1. Imidazoline receptors ................................................. 379 5.10.1.2. Agmatine ............................................................ 379 5.10.1.3. Multiple classes of adrenoceptor ....................................... 379 5.10.2. α2A-adrenoceptors ............................................................. 379 5.10.2.1. Role in the induction of antinociception ................................ 379 5.10.2.2. Additional actions .................................................... 380 5.10.3. Other α2-AR subtypes ......................................................... 381 5.10.3.1. “Non-α2A-ARs” in the modulation of nociception ....................... 381 5.10.3.2. α2B-ARs............................................................