Broad opioid antagonism amplifies disruption of locomotor function following therapy-like hindlimb stretching in spinal cord injured rats

• Published in: Spinal cord 2022-04, Vol.60 (4), p.312-319
• Main Authors: States, Gregory J. R., Keller, Anastasia, Shum-Siu, Alice, Petruska, Jeffrey C., Magnuson, David S. K.
• Format: Article
• Language: English
• Subjects: 13/51; 14/1; 14/63; 631/378; 692/698/1688/1366/1823; Analgesics, Opioid - pharmacology; Analgesics, Opioid - therapeutic use; Anatomy; Animals; Biomedical and Life Sciences; Biomedicine; Circuits; Disease Models, Animal; Female; Hindlimb; Human Physiology; Humans; Injuries; Muscles; Naltrexone; Naltrexone - pharmacology; Narcotic Antagonists - pharmacology; Narcotics; Neurochemistry; Neuropsychology; Neurosciences; Opioids; Pain perception; Pilot Projects; Rats; Rats, Sprague-Dawley; Recovery of Function - physiology; Research facilities; Spasticity; Spinal Cord; Spinal cord injuries; Spinal Cord Injuries - complications; Spinal Cord Injuries - drug therapy; Stretching
• ISSN: 1362-4393; 1476-5624
• DOI: 10.1038/s41393-021-00705-6

Study design Preclinical pilot study. Objectives To test the hypothesis that spinal opioidergic circuitry contributes to muscle stretch-induced locomotor deficits. Setting Kentucky Spinal Cord Injury Research Center, Louisville, KY, USA. Methods A pilot study with eight female Sprague-Dawley rats that received 25 g-cm T10 contusion injuries and recovered for 5 weeks. Rats were divided into two groups with one group receiving subcutaneous injections of naltrexone dissolved in saline (15 mg/kg) or an equal volume of saline. Each group received a daily 24-minute stretching protocol during weeks 6, 8, and 11 post-injury. Locomotor function was assessed throughout using the BBB Open Field Locomotor Scale. Results Consistent with previous findings, stretching reduced locomotor function in both naltrexone and saline groups. However, the loss of locomotor function appeared earlier in the naltrexone group. Animals in both groups had a similar rate of recovery following the termination of stretching. Interestingly, the administration of naltrexone did not influence acute thermal cutaneous nociceptive responses as measured by a tail-flick assay but caused a significant increase in spasticity following stretch. Conclusions The results of this study suggest that the endogenous opioid system plays a role in modulating the negative impact of muscle stretch on spinal cord motor circuitry that is vulnerable due to loss of descending input. The observed actions of the broad-spectrum opioid antagonist naltrexone imply that pharmaceuticals targeting the endogenous opioid system post-SCI may have unintended consequences.