Rescuing Sensorimotor Declines in a Rat Model of Musculoskeletal Disorders: Is Rest Best?
Authors: White Amanda R , Amin Mamta , Delany Sean , Harris Michelle , Cruz Geneva , Hobson Luke , Popoff Steven , Barbe Mary 
Published: June 2021

Overuse‐induced musculoskeletal disorders (MSDs) are a leading cause of pain and physical disability worldwide. Substance P (SubP) and its primary receptor, neurokinin‐1 (NK1R), are known for their role in pain perception, yet may also be involved in increasing tissue fibrosis. Fibrosis may be a key factor in motor dysfunction, discomfort and pain in patients with overuse‐induced MSDs. In this study, we pharmacologically targeted the SubP‐NK1R pathway in a clinically relevant operant rat model in which a high repetition, high force (HRHF) pulling task was performed.

Aim

We hypothesized that blocking the SubP‐NK1R pathway would reverse or at least reduce overuse‐induced sensorimotor declines.

Methods

Female Sprague‐Dawley rats pulled a lever bar at 48% their maximum pulling force (MPF) with self‐chosen variable force levels (+/− 10% of the 48% target) at high repetition rates. The HRHF task was performed for 12 wks (2 hrs/day, 3 days/wk). After 12 weeks, HRHF task rats were either: 1) euthanized; 2) rested 4 wks; or, 3) rested 4 wks while receiving a NK1R antagonist (NK1RA). Control rats were euthanized at matched time points as HRHF task rats. All rats were assayed every 3 weeks for reflexive grip strength and forepaw mechanical allodynia (von Frey filaments). A thermal sensitivity assay was performed in their final week before euthanasia. Serum and forelimb tissues were analyzed for fibrogenic proteins. Anti‐CD68 IHC was performed to assess macrophage infiltration in the median nerve.

Results

Reflexive grip strength declined significantly in all HRHF task animals by week 12. Rest alone improved grip strength, although NK1RA rescued it. Forepaw mechanical sensitivity changes were not evident until HRHF task week 9 (hypersensitivity to a 0.4 gram sized filament). Interestingly, hyposensitivity to 6 and 8 gram sized filaments was also present in 12 week HRHF rats. Rest (+/− NK1RA) improved these sensory deficits. Hyposensitivity to noxious warm temperatures was observed in 12 week HRHF rats. The drug was anti‐nociceptive, as warm temperature hyposensitivity was enhanced in both control+NK1RA and HRHF+Rest+NK1RA rats. Only untreated HRHF rats showed increased muscle and serum fibrogenic proteins, and CD68‐positive cells in median nerve branches, compared to control rats.

Conclusion

Past results from our lab, in which rats pulled at 55% their MPF, resulted in early musculoskeletal and nerve tissue injury and sensorimotor deficits from which the rats did not recover, even with 12 weeks of rest. We found here, for the first time, that a 4 week rest was sufficient for recovery in rats performing a slightly lower HRHF task. This recovery was also observed in HRHF+Rest+NK1RA rats; however, similar findings in control+NK1RA rats suggest that the functional improvements may be due to a drug‐induced diminished ability to sense pain and discomfort. Although our hypothesis that blocking the SubP‐NK1R pathway rescues overuse‐induced sensorimotor declines was supported, we importantly demonstrated that rest alone was just as effective, suggesting that simply reducing force effort and rest may be the most appropriate therapy for this patient population.

Support or Funding Information

NIH‐NIAMS: AR056019

ASBMR Gap Award

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.