Lactoferrin and Its Potential Impact for the Relief of Pain: A Preclinical Approach Original paper

What Was Reviewed?

This paper reviewed the potential of lactoferrin (Lf) as a novel analgesic agent with anti-nociceptive and anti-inflammatory effects, particularly in preclinical models. The authors explored lactoferrin’s mechanisms of action across various types of pain, including nociceptive, neuropathic, and nociplastic pain, and examined how Lf might modulate neuroimmune and neurochemical pathways to reduce pain perception. The paper focused on bovine lactoferrin (bLf) and human lactoferrin (hLf), assessing their safety, pharmacological actions, and signaling pathways that contribute to their analgesic effects.

Who Was Reviewed?

The review analyzed preclinical studies that used animal models, primarily rats, to evaluate lactoferrin’s effects on nociception and inflammation. These models included the formalin test, hot plate test, acetic acid-induced writhing, adjuvant-induced arthritis, and various neuropathic pain models such as chronic constriction injury (CCI), mental nerve transection (MNT), and oxaliplatin-induced neurotoxicity. Mechanistic studies involving spinal cord, peripheral nerve, and cerebrospinal fluid analyses were also reviewed to understand lactoferrin’s impact on key signaling pathways like TRAF6–NFκB and NO–cGMP–ATP-sensitive K+ channels.

What Were the Most Important Findings?

Lactoferrin consistently reduced nociceptive and neuropathic pain behaviors across multiple animal models when administered orally, intraperitoneally, or intrathecally. These effects were mediated through several key pathways. First, Lf downregulated the DAMP–TRAF6–NFκB signaling cascade, thereby suppressing pro-inflammatory cytokines (e.g., TNF-α, IL-1β) and reducing spinal inflammation. Secondly, Lf activated the nitric oxide (NO)–cGMP–ATP-sensitive K+ channel pathway, leading to neuronal hyperpolarization and decreased nociceptive signaling. Notably, the anti-nociceptive effect was reversed by nitric oxide synthase (NOS) inhibitors, confirming the pathway’s role. Thirdly, Lf modulated the opioid system, particularly µ-opioid receptors, amplifying morphine’s effects and reducing opioid tolerance. These mechanisms indicate Lf’s multi-targeted modulation of neuroimmune and sensory pathways involved in pain processing. While the paper did not explore direct changes to microbiome composition, the signaling pathways regulated by Lf are shared with microbial pattern recognition, suggesting potential for microbiome-relevant therapeutic targeting.

What Are the Implications of This Review?

This review positions lactoferrin as a promising adjunct or alternative to traditional analgesics like opioids and NSAIDs. Given its safety profile, natural origin, and ability to modulate both inflammatory and neurochemical pathways without the adverse effects typical of standard drugs, Lf holds therapeutic potential across multiple pain conditions, including those refractory to conventional treatment. Importantly, its ability to influence pathways common to microbial pattern recognition makes it a candidate for microbiome-integrated pain management strategies. The review underscores the need for human clinical trials and mechanistic microbiome studies to validate and extend these findings.