Usefulness of knockout mice to clarify the role of the opioid system in chronic pain

Abstract

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.

Linked articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

Figure 1

Schematic view of ascending and descending pain pathways, opioid locations and main effects in physiological conditions. A, A primary afferent fibres; ACC, anterior cingulate cortex; C, C primary afferent fibres; Enk, enkephalins; β‐end, β‐endorphin; Dyn, dynorphins; Hipp, hippocampus; mPFC, medial prefrontal cortex; NAcc, nucleus accumbens; NMDAR, N‐methyl‐D‐aspartate receptor; OFF, off cells; ON, on cells; PAG, periaqueductal gray; PCx, parietal cortex; RVM, rostral ventromedial medulla; S1 and S2, somatosensory cortex 1 and 2; TH, thalamus.

Figure 2

Use of opioid receptor knockout mice in chronic pain models. Cold, cold sensitivity; Heat, heat sensitivity; KO, knockout; Mechano, mechanical sensitivity; MIA, monoiodoacetate model; TCA, triciclic antidepressants. *Only results found on affective/cognitive behaviour in opioid receptor knockouts subjected to chronic pain models. Black boxes: C57BL/6 background; black‐brown boxes: C57BL/6‐129S.

Figure 3

Use of endogenous opioids knockout mice in chronic pain models. Cold, cold sensitivity; Heat, heat sensitivity; KO: knockout; Mechano, mechanical sensitivity; MIA, monoiodoacetate model; TCA, triciclic antidepressants. *Only result on affective/cognitive behaviour found in the endogenous opioid knockouts subjected to chronic pain models. Black boxes: C57BL/6 background; black‐brown boxes: C57BL/6‐129S; brown box: 129S.

Figure 4

Effects of opioid receptors activating (ON) or inhibiting (OFF) chronic inflammatory or neuropathic pain manifestations, according to knockout studies. Endogenous opioids bind to opioid receptors with different affinities. Arrow thickness indicates relative affinity for the receptor. β‐end, β‐endorphin; Dyn, dynorphins; Enk, enkephalins; NMDAR, N‐methyl‐D‐aspartate receptor. Dynorphins were described to have high affinity for KOP and low for MOP and NDMA receptors (non‐opioid receptor). Pink arrow in MOP indicates possible constitutive activity independent of ligand activation. Effects of MOP are described according to exon 2/2–3 knockout studies. Additional studies are needed to characterize affective/cognitive behaviour associated with chronic pain in these knockouts.