Several lines of knockout mice deficient in the genes encoding each component of the endogenous opioid system have been used for decades to clarify the specific role of the different opioid receptors and peptide precursors in many physiopathological conditions. The use of these genetically modified mice has improved our knowledge of the specific involvement of each endogenous opioid component in nociceptive transmission during acute and chronic pain conditions. The present review summarizes the recent advances obtained using these genetic tools in understanding the role of the opioid system in the pathophysiological mechanisms underlying chronic pain. Behavioural data obtained in these chronic pain models are discussed considering the peculiarities of the behavioural phenotype of each line of knockout mice. These studies have identified the crucial role of specific components of the opioid system in different manifestations of chronic pain and have also opened new possible therapeutic approaches, such as the development of opioid compounds simultaneously targeting several opioid receptors. However, several questions still remain open and require further experimental effort to be clarified. The novel genetic tools now available to manipulate specific neuronal populations and precise genome editing in mice will facilitate in a near future the elucidation of the role of each component of the endogenous opioid system in chronic pain.

This work was supported by the European Commission, FP7 (#HEALTH‐F2‐2013‐602891), the Spanish Ministerio de Economía y Competitividad‐MINECO (#SAF2014‐59648‐P/FEDER) and Instituto de Salud Carlos III, RETICS‐RTA (#RD12/0028/0023/FEDER), and the Generalitat de Catalunya, AGAUR (#2014‐SGR‐1547). We also acknowledge the financial support of the AGAUR (ICREA Acadèmia Award 2015) to R.M.