fibrin and Radiculopathy

OBJECTIVE Painful neuropathic injuries induce blood-spinal cord barrier (BSCB) breakdown, allowing pro-inflammatory serum molecules to cross the BSCB, which contributes to nociception. The goal of these studies was to determine whether the blood-borne serine protease thrombin also crosses a permeable BSCB, contributing to nociception through its activation of protease-activated receptor-1 (PAR1). METHODS A 15-minute C-7 nerve root compression, which induces BSCB breakdown and painful behaviors by Day 1, was administered in the rat (n = 10); sham operation (n = 11) and a 3-minute compression (n = 10) that does not induce sensitivity were administered as controls. At Day 1 after root compression, spinal cord tissue was co-immunolabeled for fibrin/fibrinogen, the enzymatic product of thrombin, and IgG, a serum protein, to determine whether thrombin acts in areas of BSCB breakdown. To determine whether spinal thrombin and PAR1 contribute to hyperalgesia after compression, the thrombin inhibitor hirudin and the PAR1 antagonist SCH79797, were separately administered intrathecally before compression injuries (n = 5-7 per group). Rat thrombin was also administered intrathecally with and without SCH79797 (n = 6 per group) to determine whether spinal thrombin induces hypersensitivity in naïve rats through PAR1. RESULTS Spinal fibrin(ogen) was elevated at Day 1 after root compression in regions localized to BSCB breakdown and decreased in those regions by Day 7. Blocking either spinal thrombin or PAR1 completely prevented compression-induced hyperalgesia for 7 days. Intrathecal thrombin induced transient pain that was prevented by blocking spinal PAR1 before its injection. CONCLUSIONS The findings of this study suggest a potent role for spinal thrombin and its activation of PAR1 in pain onset following neuropathic injury.

Topics: Animals; Antithrombins; Capillary Permeability; Central Nervous System Agents; Cervical Vertebrae; Disease Models, Animal; Fibrin; Hirudins; Hyperalgesia; Injections, Spinal; Male; Pain; Pain Measurement; Peripheral Nervous System Diseases; Pyrroles; Quinazolines; Radiculopathy; Rats, Sprague-Dawley; Receptor, PAR-1; Spinal Cord

Nerve root compression is a common cause of radiculopathy and induces persistent pain. Mammalian fibrin is used clinically as a coagulant but presents a variety of risks. Fish fibrin is a potential biomaterial for neural injury treatment because it promotes neurite outgrowth, is non-toxic, and clots readily at lower temperatures. This study administered salmon fibrin and thrombin following nerve root compression and measured behavioral sensitivity and glial activation in a rat pain model. Fibrin and thrombin each significantly reduced mechanical allodynia compared to injury alone (p < 0.02). Painful compression with fibrin exhibited allodynia that was not different from sham for any day using stimulation by a 2 g filament; allodynia was only significantly different (p < 0.043) from sham using the 4 g filament on days 1 and 3. By day 5, responses for fibrin treatment decreased to sham levels. Allodynia following compression with thrombin treatment were unchanged from sham at any time point. Macrophage infiltration at the nerve root and spinal microglial activation were only mildly modified by salmon treatments. Spinal astrocytic expression decreased significantly with fibrin (p < 0.0001) but was unchanged from injury responses for thrombin treatment. Results suggest that salmon fibrin and thrombin may be suitable biomaterials to mitigate pain.

Topics: Animals; Cervical Vertebrae; Densitometry; Fibrin; Hyperalgesia; Immunohistochemistry; Male; Pain; Radiculopathy; Rats; Salmon; Spinal Nerve Roots; Thrombin

Topics: Animals; Arachnoiditis; Back Pain; Fibrin; Humans; Inflammation; Intervertebral Disc Displacement; Radiculopathy