Figure 2. Inflammation induced migration of opioid-producing leukocytes and opioid secretion.

Resident macrophages of the inflammed tissue release chemokine gradient to recruit neutrophils form the blood stream. Chemokine secretion leads to upregulation of adhesion molecules (P-selectin, ICAM-1 etc.) on the capillary endothelium which facilitates neutrophil rolling, adhesion and extravasation. Once extravasated, leukocytes can be stimulated by releasing agents such as corticotropin-releasing factor (CRF), interleukin-1β (IL-1) and/or noradrenaline (NA). CRF, IL-1, and NA (derived from sympathetic neurons) elicit opioid release by activating their respective receptors on leukocytes. Opioids bind to peripheral opioid receptors (produced in dorsal root ganglia and transported to peripheral endings of sensory neurons) and produce analgesia by inhibiting the excitability of these neurons. Opioid agonists have easier access to neuronal opioid receptors during inflammation because inflammation disrupts the perineurium (normally a rather impermeable sheath encasing peripheral-nerve fibers). Arrow in the blood vessel and sensory neuron indicates the direction of the events.