Injury to peripheral nerves often leads to abnormal pain states (hyperalgesia, allodynia and spontaneous pain), which can remain long after the injury heals. Although opioid agonists remain the gold standard for the treatment of moderate to severe pain, they show reduced efficacy against neuropathic pain. In addition to analgesia, opioid use is also associated with hyperalgesia and analgesia tolerance, whose underlying mechanisms share some commonalities with nerve injury-induced hypersensitivity. Here, we reviewed up-to-day research exploring the contribution of mu-opioid receptor (MOR) on the pathophysiology of neuropathic pain and on analgesic opioid actions under these conditions. We focused on the specific contributions of MOR populations at peripheral, spinal and supraspinal level. Moreover, evidences of neuroplastic changes that may underlie the low efficacy of MOR agonists under neuropathic pain conditions are reviewed and discussed. Sensitization processes leading to pain hypersensitivity, molecular changes in signalling pathways triggered by MOR and glial activation are some of these mechanisms elicited by both nerve injury and opioid exposure. Nerve injury-induced pain hypersensitivity might be masking the initial analgesic effects of opioid agonists, and alternatively, sustained opioid treatment to individuals already suffering from neuropathic pain could aggravate their pathophysiological state. Finally, some combined therapies that can increase opioid analgesic effectiveness in neuropathic pain treatment are highlighted. SIGNIFICANCE: This review provides evidence of the low benefit of opioid monotherapy in neuropathic pain and analyses the reasons of this reduced effectiveness. Opioid agonists along with drugs targeted to block the sensitization processes induced by MOR stimulation might result in a better management of neuropathic pain.

We acknowledge the financial support of the European Commission FP7. Grant Number: #HEALTH‐F2‐2013‐602891; Spanish Ministry of Science, Innovation and Universities. Grant Number: #SAF2017‐84060‐R‐AEI/FEDER‐UE; Instituto de Salud Carlos III. Grant Number: RETICS/RTA #RD16/0017; Catalan Government AGAUR. Grant Numbers: #ICREA Acadèmia‐2015, #2017‐SGR‐669; Spanish MECD