When does acute pain become chronic? C Voscopoulos, M Lema  British Journal of Anaesthesia  Volume 105, Pages i69-i85 (December 2010) DOI: 10.1093/bja/aeq323 Copyright © 2010 The Author(s) Terms and Conditions

Fig 1 Peripheral mechanisms of nerve fibre sensitization. Understanding the ability of peripheral neurones to sensitize is complex given the number of known ligand- and voltage-gated ion channels. However, many of these receptors use protein kinases A and C (PKA, PKC) signalling pathways. Vanilloid type 1 receptor (VR1), 5-hydroxytryptamine receptors (5HT), Histamine type 1 (H1), Prostaglandin E2 (PGE2), Prostanoid receptor EP subtype (EP), bradykinin receptors (B1/B2), interleukin-1 beta (IL-1β), interleukin-1 receptor (IL1-R), nerve growth factor (NGF), tyrosine kinase A receptor (TrkA), adenosine triphosphate (ATP), purinergic receptor subtype P2X (P2X), hydrogen ion (H+), calcium (Ca2+), protein tetrodotoxin-resistant voltage-gated sodium channel (TTXr), tetrodotoxin-sensitive voltage-gated sodium channel (TTXs), substance P (Sub P), acid-sensing channel (ASIC). Used with Permission by Elsevier Limited. Modified from Costigan M, Woolf CJ. Pain: molecular mechanisms. J Pain 2000 (Suppl. 3):35–44. British Journal of Anaesthesia 2010 105, i69-i85DOI: (10.1093/bja/aeq323) Copyright © 2010 The Author(s) Terms and Conditions

Fig 2 Peripheral and central roles of prostaglandins and cyclo-oxygenase-2 (COX-2) in pain perception and sensitization. COX-2 plays both a peripheral and central role in pain perception and sensitization. However, inflammation-evoked spinal hyperexcitability might be more related to spinal COX-2 causing the metabolism of 2-arachidonoylglycerol (2-AG) to prostaglandin E2 subtype G (PGE2-G), and other endocannabinoids to derivatives that bind prostaglandin receptors, than to spinal prostaglandin synthesis. Interleukin-1 beta (IL-1β), N-methyl-d-aspartate receptor (NMDA), calcium (Ca2+), nitric oxide synthetase (NOS). Modified and used with permission from Raymond Sinatra MD, PhD. British Journal of Anaesthesia 2010 105, i69-i85DOI: (10.1093/bja/aeq323) Copyright © 2010 The Author(s) Terms and Conditions