Behavioral and inflammatory sex differences revealed by celecoxib nanotherapeutic treatment of peripheral neuroinflammation

Neuropathic pain affects millions of people worldwide, yet the molecular mechanisms of how it develops and persists are poorly understood. Given that males have historically been utilized as the primary sex in preclinical studies, less is known about the female neuroinflammatory response to injury, formation of pain, or response to pain-relieving therapies. Macrophages contribute to the development of neuroinflammatory pain via the activation of their cyclooxygenase-2 (COX-2) enzyme, which leads to the production of prostaglandin E-2 (PGE(2)). PGE(2) activates nociception and influences additional leukocyte infiltration. Attenuation of COX-2 activity decreases inflammatory pain, most commonly achieved by nonsteroidal anti-inflammatory drugs (NSAIDs), yet NSAIDs are considered ineffective for neuropathic pain due to off target toxicity. Using chronic constriction injury of the rat sciatic nerve, we show that males and females exhibit quantitatively the same degree of mechanical allodynia post injury. Furthermore, a low-dose nanotherapeutic containing the NSAID celecoxib is phagocytosed by circulating monocytes that then naturally accumulate at sites of injury as macrophages. Using this nanotherapeutic, we show that treated males exhibit complete reversal of hypersensitivity, while the same dose of nanotherapeutic in females provides an attenuated relief. The difference in behavioral response to the nanotherapy is reflected in the reduction of infiltrating macrophages at the site of injury. The observations contained in this study reinforce the notion that female neuroinflammation is different than males.

Automated summary

Neuropathic pain is a significant problem affecting millions of people worldwide, but the molecular mechanisms behind its development and persistence are not well understood. This study investigates the neuroinflammatory response to injury and pain relief therapies in males and females. The research shows that a low-dose nanotherapeutic containing an NSAID can effectively reduce pain in both males and females, although the relief is weaker in females. These findings suggest that the neuroinflammatory response differs between males and females.