title: Ketorolac reduces spinal astrocytic activation and PAR1 expression associated with attenuation of pain after facet joint injury.
abstract: Chronic neck pain affects up to 70% of persons, with the facet joint being the most common source. Intra-articular injection of the non-steroidal anti-inflammatory drug ketorolac reduces post-operative joint-mediated pain; however, the mechanism of its attenuation of facet-mediated pain has not been evaluated. Protease-activated receptor-1 (PAR1) has differential roles in pain maintenance depending on the type and location of painful injury. This study investigated if the timing of intra-articular ketorolac injection after painful cervical facet injury affects behavioral hypersensitivity by modulating spinal astrocyte activation and/or PAR1 expression. Rats underwent a painful joint distraction and received an injection of ketorolac either immediately or 1 day later. Separate control groups included injured rats with a vehicle injection at day 1 and sham operated rats. Forepaw mechanical allodynia was measured for 7 days, and spinal cord tissue was immunolabeled for glial fibrillary acidic protein (GFAP) and PAR1 expression in the dorsal horn on day 7. Ketorolac administered on day 1 after injury significantly reduced allodynia (p=0.0006) to sham levels, whereas injection immediately after the injury had no effect compared with vehicle. Spinal astrocytic activation followed behavioral responses and was significantly decreased (p=0.009) only for ketorolac given at day 1. Spinal PAR1 (p=0.0025) and astrocytic PAR1 (p=0.012) were significantly increased after injury. Paralleling behavioral data, astrocytic PAR1 was returned to levels in sham only when ketorolac was administered on day 1. Yet, spinal PAR1 was significantly reduced (p<0.0001) by ketorolac independent of timing. Spinal astrocyte expression of PAR1 appears to be associated with the maintenance of facet-mediated pain.
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Dong
authors.forename: Jenell R
authors.initials: JR
authors.lastname: Smith
authors.forename: Beth A
authors.initials: BA
authors.lastname: Winkelstein
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D007270:Injections, Intra-Articular; D020910:Ketorolac / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010149:Postoperative Pain / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044463:Receptor, PAR-1 / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D021801:Zygapophyseal Joint / Q000293:injuries*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005904:Glial Fibrillary Acidic Protein; D044463:Receptor, PAR-1; D020910:Ketorolac