Pharmacologic and Toxicologic Impacts of Formoterol on Neuropathic Pain in Models of Headache and Spinal Cord Injury

Abstract

There are approximately 18,000 new cases of spinal cord injury (SCI) in the United States every year alone. Up to 80% of these patients report suffering from chronic pain which is poorly managed with the current treatment plans and analgesics. Nearly 40% of the patient cohort experiencing chronic pain would trade the chance of functional recovery for pain relief. It has been shown previously that treatment with formoterol, an FDA-approved β2-adrenergic receptor agonist, improves recovery post-SCI in mice. However, the effects of formoterol on neuroinflammation and neuropathic pain have yet to be discerned. Female mice were subjected to moderate (60 kdyn) or severe (80 kdyn) SCI followed by daily treatment with either formoterol (0.3 mg/kg, i.p.) or vehicle beginning 8-hours after injury. Expression of markers of neuroinflammation were decreased in the formoterol treated mice; thermal hyperalgesia and mechanical allodynia, as measured via Von Frey filaments and Hargreaves infrared apparatus, was also ameliorated upon treatment with formoterol. During this time, mice were evaluated for headache-like behavior via Von Frey filament application and found to be experiencing headache at all time-points tested. Treatment with formoterol for 7 days decreased levels of endogenous cannabinoids AEA and 2-AG; when mice were given inhibitors of the MAGL and FAAH endocannabinoid enzymes, a reversal of this headache-like behavior was observed. This suggests that formoterol is exerting an analgesic effect in regards to mechanical allodynia and thermal hyperalgesia post-SCI, while also inducing headache via interaction with the endocannabinoid system.