Opioids and a Neuro-Vascular-Immune Axis.

Opioid-based agents represent the cornerstone of analgesia in modern clinical practice. Additionally however opioids produce a range of unwelcome side-effects including immunomodulation. It has been suggested that this immunomodulation may result either as a direct effect of opioids on circulating immune cells or via a central action. Meanwhile studies show that classical opioid receptors are up-regulated in peripheral inflammation, while endogenous opioids are released from circulating immune cells producing local analgesia. Expression of opioid receptors on immune cells however remains contentious. This thesis has made a significant contribution to understanding the interaction between opioids and a neurovascularimmune axis by employing radioligand binding, flow cytometry and polymerase chain reaction techniques to make a systematic and detailed examination of the expression of the classical opioid receptors (MOP, DOP and KOP) and the non-classical opioid receptor (NOP) and the precursor for its endogenous ligand N/OFQ (ppN/OFQ) in the peripheral blood mononuclear cells (PBMCs) of healthy volunteers. Using these techniques we have shown (1) that naïve human PBMCs do not express classical opioid receptors, (2) that PCR techniques support the view that PBMCs do express gene transcripts for NOP and ppN/OFQ. In an additional clinical study during a profound vascular insult we have used quantitative PCR and radioimmunoassay techniques to follow the expression of the opioid receptors and native N/OFQ throughout a septic episode in patients admitted to the intensive care unit (ICU). Here we report for the first time an elevation in plasma N/OFQ concentration in non-survivors of sepsis requiring ICU admission, 3.0 [2.5 – 5.0]pg ml-1 in non-survivors vs. 1.0 [1.0 – 2.5]pg ml-1 in survivors (p=0.028). Similarly we are first in reporting an elevation in plasma N/OFQ following major abdominal surgery in septic patients. These findings lead us to suggest an amendment to the previously proposed neuroimmune axis to include the N/OFQ-NOP system.