title: Periaqueductal Grey EP3 Receptors Facilitate Spinal Nociception in Arthritic Secondary Hypersensitivity.
abstract: Descending controls on spinal nociceptive processing play a pivotal role in shaping the pain experience after tissue injury. Secondary hypersensitivity develops within undamaged tissue adjacent and distant to damaged sites. Spinal neuronal pools innervating regions of secondary hypersensitivity are dominated by descending facilitation that amplifies spinal inputs from unsensitized peripheral nociceptors. Cyclooxygenase-prostaglandin (PG) E2 signaling within the ventrolateral periaqueductal gray (vlPAG) is pronociceptive in naive and acutely inflamed animals, but its contributions in more prolonged inflammation and, importantly, secondary hypersensitivity remain unknown. In naive rats, PG EP3 receptor (EP3R) antagonism in vlPAG modulated noxious withdrawal reflex (EMG) thresholds to preferential C-nociceptor, but not A-nociceptor, activation and raised thermal withdrawal thresholds in awake animals. In rats with inflammatory arthritis, secondary mechanical and thermal hypersensitivity of the hindpaw developed and was associated with spinal sensitization to A-nociceptor inputs alone. In arthritic rats, blockade of vlPAG EP3R raised EMG thresholds to C-nociceptor activation in the area of secondary hypersensitivity to a degree equivalent to that evoked by the same manipulation in naive rats. Importantly, vlPAG EP3R blockade also affected responses to A-nociceptor activation, but only in arthritic animals. We conclude that vlPAG EP3R activity exerts an equivalent facilitation on the spinal processing of C-nociceptor inputs in naive and arthritic animals, but gains in effects on spinal A-nociceptor processing from a region of secondary hypersensitivity. Therefore, the spinal sensitization to A-nociceptor inputs associated with secondary hypersensitivity is likely to be at least partly dependent on descending prostanergic facilitation from the vlPAG.
  
  
  
  After tissue damage, sensitivity to painful stimulation develops in undamaged areas (secondary hypersensitivity). This is found in many painful conditions, particularly arthritis. The periaqueductal gray (PAG) is an important center that controls spinal nociceptive processing, on which secondary hypersensitivity depends. Prostaglandins (PGs) are mediators of inflammation with pronociceptive actions within the PAG under normal conditions. We find that secondary hindpaw hypersensitivity in arthritic rats results from spinal sensitization to peripheral A-nociceptor inputs. In the PAG of arthritic, but not naive, rats, there is enhanced control of spinal A-nociceptor processing through PG EP3 receptors. The descending facilitatory actions of intra-PAG PGs play a direct and central role in the maintenance of inflammatory secondary hypersensitivity, particularly relating to the processing of A-fiber nociceptive information.
authors: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors: R A R
authors: 0000-0002-6433-5948
authors: RA
authors: Drake
authors: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors: J L
authors: JL
authors: Leith
authors: Arthritis Research UK Pain Centre and School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom, and.
authors: F
authors: F
authors: Almahasneh
authors: Neurosciences CEDD, GlaxoSmithKline, Harlow CM19 5AW, United Kingdom.
authors: J
authors: J
authors: Martindale
authors: Neurosciences CEDD, GlaxoSmithKline, Harlow CM19 5AW, United Kingdom.
authors: A W
authors: AW
authors: Wilson
authors: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors: B
authors: 0000-0002-0268-6419
authors: B
authors: Lumb
authors: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom, Arthritis Research UK Pain Centre and School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom, and Lucy.Donaldson@nottingham.ac.uk.
authors: L F
authors: 0000-0002-4242-5790
authors: LF
authors: Donaldson
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D019540:Area Under Curve; D001168:Arthritis / Q000139:chemically induced / Q000150:complications*; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000633:toxicity; D006930:Hyperalgesia / Q000503:physiopathology*; D007660:Ketoprofen / Q000494:pharmacology; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000502:physiology; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D009474:Neurons / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000502:physiology; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C506966:GW 678248; D009570:Nitriles; D012333:RNA, Messenger; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013449:Sulfonamides; D005620:Freund's Adjuvant; D007660:Ketoprofen
keywords: arthritis; descending facilitation; inflammation; periaqueductal grey; prostaglandins; secondary hyperalgesia