Background: The peripheral immune-derived opioid analgesic pathway has been well established
as a novel target in the clinical pain management of a number of painful pathologies, including acute
inflammatory pain, neuropathic pain, and rheumatoid arthritis.
Objective: Our objective was to engineer targeted nanoparticles that mimic immune cells in peripheral
pain control to deliver opioids, in particular loperamide HCl, specifically to peripheral opioid receptors
to induce analgesic and anti-inflammatory actions for use in painful inflammatory conditions. This
peripheral analgesic system is devoid of central opioid mediated side effects (e.g., respiratory depression,
sedation, dependence, tolerance).
Study Design: A randomized, double blind, controlled animal trial.
Methods: Thirty-six adult male Wistar rats (200 - 250 g) were randomly divided into 6 groups: loperamide
HCl-encapsulated anti-ICAM-1 immunoliposomes, naloxone methiodide + loperamide HCl-encapsulated antiICAM-1 immunoliposomes, loperamide HCl-encapsulated liposomes, empty anti-ICAM-1 immunoliposomes,
empty liposomes, and loperamide solution. Animals received an intraplantar injection of 150 µL Complete
Freund’s Adjuvant (CFA) into the right hindpaw and experiments were performed 5 days post-CFA injection,
which corresponded to the peak inflammatory response. All formulations were administered intravenously
via tail vein injection. The dose administered was 200 µL, which equated to 0.8 mg of loperamide HCl for the
loperamide HCl treatment groups (sub-therapeutic dose). Naloxone methiodide (1 mg/kg) was administered
via intraplantar injection, 15 minutes prior to loperamide-encapsulated anti-ICAM-1 immunoliposomes. An
investigator blinded to the treatment administered assessed the time course of the antinociceptive and antiinflammatory effects using a paw pressure analgesiometer and plethysmometer, respectively. Biodistribution
studies were performed 5 days post-CFA injection with anti-ICAM-1 immunoliposomes and control liposomes
via tail vein injection using liquid scintillation counting (LSC).
Results: Administration of liposomes loaded with loperamide HCl, and conjugated with antibody to
intercellular adhesion molecule-1 (anti-ICAM-1), exerted analgesic and anti-inflammatory effects exclusively
in peripheral painful inflamed tissue. These targeted nanoparticles produced highly significant analgesic
and anti-inflammatory effects over the 48 hour time course studied following intravenous administration
in rats with Complete Freund’s Adjuvant-induced inflammation of the paw. All control groups showed no
significant antinociceptive or anti-inflammatory effects. Our biodistribution study demonstrated specific
localization of the targeted nanoparticles to peripheral inflammatory tissue and no significant uptake into
the brain.
Limitations: In vivo studies were performed in the well-established rodent model of acute
inflammatory pain. We are currently studying this approach in chronic pain models known to have
clinical activation of the peripheral immune-derived opioid response.
Conclusions: The study presents a novel approach of opioid delivery specifically to injured tissues for
pain control. The study also highlights a novel anti-inflammatory role for peripheral opioid targeting,
which is of clinical relevance. The potential also exists for the modification of these targeted nanoparticles
with other therapeutic compounds for use in other painful conditions.
Key words: Pain, inflammation; immune cells, opioids, ICAM-1, loperamide, targeted drug delivery,
immunoliposomes
Targeted Nanoparticles that Mimic Immune
Cells in Pain Control Inducing Analgesic and
Anti-inflammatory Actions: A Potential Novel
Treatment of Acute and Chronic Pain Conditions
