An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury.
Morphine is one of the most commonly prescribed medications for the treatment of chronic pain after a spinal cord injury (SCI). Despite widespread use, however, little is known about the secondary consequences of morphine use after SCI. Unfortunately, our previous studies show that administration of a single dose of morphine, in the acute phase of a moderate spinal contusion injury, significantly attenuates locomotor function, reduces weight gain, and produces symptoms of paradoxical pain (Hook et al., 2009). The current study focused on the cellular mechanisms that mediate these effects. Based on data from other models, we hypothesized that pro-inflammatory cytokines might play a role in the morphine-induced attenuation of function. Experiment 1 confirmed that systemic morphine (20 mg/kg) administered one day after a contusion injury significantly increased expression levels of spinal IL-1β 24 h later. Experiment 2 extended these findings, demonstrating that a single dose of morphine (90 μg, i.t.) applied directly onto the spinal cord increased expression levels of spinal IL-1β at both 30 min and 24 h after administration. Experiment 3 showed that administration of an interleukin-1 receptor antagonist (IL-1ra, i.t.) prior to intrathecal morphine (90 μg), blocked the adverse effects of morphine on locomotor recovery. Further, pre-treatment with 3 μg IL-1ra prevented the increased expression of at-level neuropathic pain symptoms that was observed 28 days later in the group treated with morphine-alone. However, the IL-1ra also had adverse effects that were independent of morphine. Treatment with the IL-1ra alone undermined recovery of locomotor function, potentiated weight loss and significantly increased tissue loss at the injury site. Overall, these data suggest that morphine disrupts a critical balance in concentrations of pro-inflammatory cytokines in the spinal cord, and this undermines recovery of function.
Department of Psychology, Texas A&M University, College Station, TX 77843-4235, USA. michellehook@tamu.edu
Michelle A
MA
Hook
Stephanie N
SN
Washburn
Georgina
G
Moreno
Sarah A
SA
Woller
Denise
D
Puga
Kuan H
KH
Lee
James W
JW
Grau
D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007278:Injections, Spinal; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009128:Muscle Spasticity / Q000517:prevention & control; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D012677:Sensation / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
D000701:Analgesics, Opioid; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D009020:Morphine