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) E 2 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.

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats

“…Here we show that, in neuropathic animals, peripherally evoked spinal dorsal horn wide dynamic range (WDR) neurons are inhibited by PrL-P neuronal activity confirming that the PrL is able to engage descending pain modulatory systems that originate in the PAG. Spinal WDR neurons are a known target of descending modulatory systems and their activity correlates well with both withdrawal reflexes and pain perception (Maixner et al, 1986;You et al, 2003;McMullan and Lumb, 2006a;Drake et al, 2016).…”

VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis

“…The study design did not permit the full suite of behaviour measurements and tissue collection on the same day. In our experience of this model secondary mechanical allodynia peaks after one week ( Drake et al, 2016 ) and is maintained to at least day 14 therefore we selected time points for tissue analysis when secondary pain was established. Mouse spinal cords were perfuse-fixed as above and dissected following the completion of the behavioral tests on day 14, a time point at which significant differences in contralateral behavior were observed.…”

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats

“…Direct corticofugal projections from the mPFC to the midbrain link it to the DPMS to provide a route to pain state regulation ( An et al, 1998 ; Huang et al, 2019 ). The midbrain periaqueductal grey (PAG) is a core component of the DPMS able to facilitate and/or inhibit spinal nociceptive processing via pain modulatory brainstem nuclei including the rostral ventromedial medulla and locus coeruleus ( Mantyh, 1983 ; Waters and Lumb, 2008 ; Ossipov et al, 2010 ; Drake et al, 2016 ). Notably, altered functional connectivity between the mPFC and PAG is observed in human patients with musculoskeletal, neuropathic, and inflammatory chronic pain, suggesting that altered cortical control may contribute to maladaptation of the DPMS and that this mechanism may be relevant to chronic pain in general ( Cifre et al, 2012 ; Yu et al, 2014 ; Chen et al, 2017 ; Mills et al, 2018 ; Segerdahl et al, 2018 ).…”