Opioids and the neuroimmune axis

Clinically opioids are immunomodulatory where a general depression is reported. In addition, immune cells carry endogenous opioid peptides to sites of inflammation where opioid receptors on peripheral nerves are upregulated. Release of these endogenous opioids produces a degree of analgesia and completes the neuroimmune axis. The expression of opioid receptors on immune cells that deliver these opioid peptides, is contentious and is the basis of this short review. There are several papers reporting expression of opioid receptors on peripheral blood mononuclear cells （PBMCs） using a variety of in vitro biochemical/pharmacological techniques. Equally there are studies failing to detect these receptors. We have recently undertaken a detailed volunteer study to determine the expression of classical naloxone sensitive MOP, DOP and KOP and non-classical naloxone insensitive NOP receptors. We initially focused our attention on the MOP receptor as the main clinical analgesic target. Using radioligand binding, FACS with opioid receptor antibodies and PCR we have failed to detect all classical opioid receptors. In contrast, using PCR techniques the non-classical NOP receptor is present in all volunteer samples examined along with its endogenous peptide ligand nociceptin/orphanin F/Q （N/OFQ）. As both the peptide （N/OFQ） and receptor （NOP） are present we suggest that there may be a feedback loop such that peripherally delivered N/OFQ（ to infl ammatory site） would produce both a classical analgesic response and then feedback to modulate PMBC function. The nature of that function remains to be determined but could include release of further N/OFQ, activation of other immune cells or chemotaxis. Opioids have been used by man for centuries for the relief of pain. Morphine is the most widely used opioid in the clinic and is considered the gold standard to which all others are compared. In addition to producing analgesia, opioid administration also produces other eff ects including; respiratory depression, gastrointestinal-inhibition, tolerance and dependence and immunomodulationbasic summaries see1-4）. Patients receiving long term opioid treatment display signs of immunodepression; it has been suggested that this may occur either as a direct eff ect of opioids on circulating immune cells or via a central action （see below）. Neuronal opioid receptors are up-regulated in peripheral infl ammation and Stein and colleagues（ in particular） have shown that release of these endogenous opioids from circulating immune cells produces a degree of analgesia and complete the neuroimmune axis5）, i.e., immunomodulation of neuronal activity. The expression of opioid receptors on the circulating immune cells that deliver these opioid peptides remains unclear and is the focus of this short review