Low-dose NSAIDs reduce pain via macrophage targeted nanoemulsion delivery to neuroinflammation of the sciatic nerve in rat

Abstract

Neuroinflammation involving macrophages elevates Prostaglandin E, associated with neuropathic pain. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) inhibits cyclooxygenase, reducing PGE. However, NSAIDs cause physiological complications. We developed nanoemulsions incorporating celecoxib and near infrared dye. Intravenous injected nanoemulsion is incorporated into monocytes that accumulate at the injury; revealed in live animals by fluorescence. A single dose (celecoxib 0.24 mg/kg) provides targeted delivery in chronic constriction injury rats, resulting in significant reduction in the visualized inflammation, infiltration of macrophages, COX-2 and PGE. Animals exhibit relief from hypersensitivity persisting at least four-days. The total body burden of drug is reduced by >2000 fold over oral drug delivery.

Targeted cyclooxygenase-2 inhibiting nanomedicine results in pain-relief and differential expression of the RNA transcriptome in the dorsal root ganglia of injured male rats

“…Peripheral nerve injury was induced (this was designated “day 0”) using CCI as first described by Bennett and Xie 9 and adapted previously. 4 , 5 , 14 , 15 Briefly, CCI causes inflammation and subsequent pain when chromic gut sutures are loosely tied around the common sciatic nerve in the animal’s hindleg. Animals are anesthetized with inhaled isoflurane and oxygen.…”

“…Mechanical allodynia testing of both hind-paws was conducted using von Frey monofilaments of increasing diameters using the up-down method as described previously. 5 , 14 , 15 , 26 Behavioral testing was conducted twice before surgery (day 0), and days 2 through 12 after surgery, with a rest day on the day of and after surgery. The 50% paw withdrawal threshold was calculated and treatment groups were analyzed by two-way analysis of variance (ANOVA) and post hoc Tukey testing using GraphPad Prism 8.0.…”

“…CXB-NE and drug-free nanoemulsion (DF-NE) (vehicle) 5 , 14 , 15 , 25 , 27 treatments were randomized and blinded to investigators. Nanoemulsion was administered on day 8 when the animal is reaching a plateau of pain behavior.…”

“…We have previously shown that localized delivery of a single micro-dose (0.24 mg/kg) of CXB in nanoemulsion, which is incorporated in circulating macrophages/monocytes that then naturally accumulate at the site of injury provides up to six days of pain relief. 5 , 14 , 15 , 25 An important feature is that the nanomedicine delivers drug to the affected injured nerve. 5 , 14 , 15 This creates a unique opportunity to assess drug effects on cellular expression of RNAs when the drug is present at the distal injury and virtually no other parts of the peripheral nervous system.…”

“… 5 , 14 , 15 , 25 An important feature is that the nanomedicine delivers drug to the affected injured nerve. 5 , 14 , 15 This creates a unique opportunity to assess drug effects on cellular expression of RNAs when the drug is present at the distal injury and virtually no other parts of the peripheral nervous system. With this approach, we have been able to reveal transcriptome changes in the DRG associated with CXB-NE.…”