Periaqueductal Grey EP3 Receptors Facilitate Spinal Nociception in Arthritic Secondary Hypersensitivity

Robert A R Drake, J Lianne Leith, F Almahasneh, Joanne Martindale, Andrew W Wilson, Bridget M Lumb, Lucy F Donaldson

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Descending controls on spinal nociceptive processing play a pivotal role in shaping the pain experience following 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 un-sensitized peripheral nociceptors. Cyclooxygenase–prostaglandin E2 signaling within the ventrolateral periaqueductal grey (vlPAG) is pro-nociceptive in naïve and acutely inflamed animals but its contributions in more prolonged inflammation and, importantly, secondary hypersensitivity remain unknown. In naïve rats, prostaglandin EP3 receptor (EP3R) antagonism in vlPAG modulated noxious withdrawal reflex (EMG) thresholds to preferential C-, 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 hind-paw developed, and this was associated with spinal sensitization to Anociceptor 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 naïve 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 naïve and arthritic animals but gains in effects on spinal A-nociceptor processing from a region of secondary hypersensitivity. Thus 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.
Original languageEnglish
Pages (from-to)9026 –9040
Number of pages15
JournalJournal of Neuroscience
Issue number35
Publication statusPublished - 31 Aug 2016


  • Periaqueductal Grey
  • Descending Facilitation
  • Prostaglandins
  • Arthritis
  • Secondary hyperalgesia
  • A-nociceptors


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