An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury

Abstract

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 hrs 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 hrs 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.

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

“…In the absence of norBNI, morphine-treated rats showed decreased locomotor recovery relative to vehicle-treated controls, replicating our previous studies. 2,4 Moderate to high doses of norBNI (0.08 and 0.32 lmol respectively), however, blocked the effects of morphine on locomotor recovery. Importantly, at these doses, morphine administration still produced significant analgesia.…”

“…[1][2][3][4][5] To address this, norBNI was administered as an adjuvant to morphine treatment 24 h following SCI, and locomotor recovery was monitored for a 21 day period. Locomotor scores collected before treatment on day 1 did not differ significantly across groups (F [7, Fig.…”

“…[1][2][3][4][5] As opioids are currently among the most effective analgesics for the treatment of pain in the acute phase of SCI, it is essential that we identify the mechanisms underlying these adverse side effects and improve the safety of these medications.…”

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

“…If a clinically used compound or one of its metabolites possesses such TLR agonistic activity, side effects of the drug may be attributable to such undefined TLR agonist activity. In the case of opioids, such opioid-induced central immune signaling contributes to adverse recovery in preclinical models of spinal cord injury (Hook et al, 2009(Hook et al, , 2011. Moreover, the shared central immune signaling properties of opioids with other drugs of abuse, such as methamphetamine, also raise the possibility that this drug-induced central immune signaling process may be a common phenomenon across drugs of abuse, resulting in amplification of drug-mediated activation of the mesolimbic dopamine reward pathway.…”

Neurobiological Effects of Morphine after Spinal Cord Injury

“…[5][6][7] Moreover, these adverse effects are not limited to IT morphine administration. Woller and colleagues 8 showed that self-administration of high doses of intravenous (IV) morphine, a more clinically relevant route of administration, also significantly undermined locomotor recovery after injury.…”