Autophagy in superficial spinal dorsal horn accelerates the cathepsin B-dependent morphine antinociceptive tolerance

Abstract

Opioids are the most widely used analgesics in the treatment of severe acute and chronic pain. However, opioids have many adverse side effects, including the development of antinociceptive tolerance after long-term use. The antinociceptive tolerance of opioids has limited their clinical use. A recent study has reported that autophagy is responsible for morphine-induced neuronal injury. However, little is known about the role of autophagy in morphine antinociceptive tolerance. In the present study, chronic morphine administration was found to induce the expression of autophagy-related proteins, including Beclin1 and microtubule-associated protein light chain 3 (LC3)-II, in GABAergic interneurons in the superficial layer (lamina I-II) of the spinal cord. A single intrathecal administration of autophagy inhibitors, 3-methyladenine (3MA) or wortmannin, inhibited the development of antinociceptive tolerance in a dose-dependent manner. Autophagy in the lamina I-II neurons was associated with increased level of cathepsin B (CatB), a lysosomal cysteine protease. The pharmacological blockade or gene deletion of CatB markedly prevented the development of morphine antinociceptive tolerance. Furthermore, the intrathecal administration of 3MA suppressed the upregulation of CatB 5 days after morphine administration. Finally, CatB deficiency inhibited the increased release probability of glutamate in the lamina I neurons after chronic morphine treatment. These observations suggest that the dysfunction of the spinal GABAergic system induced by CatB-dependent excessive autophagy is partly responsible for morphine antinociceptive tolerance following chronic treatment.

Atg5- and Atg7-dependent autophagy in dopaminergic neurons regulates cellular and behavioral responses to morphine

“…A previous study found that chronic morphine administration induced autophagy in GABAergic interneurons from the spinal cord; 18 however, we did not observe autophagy in the midbrain GABAergic interneurons in this study. The apparent discrepancy might be caused by several factors that are crucial for drug-induced plasticity, such as the age of the mice (8-wkold C57BL/6 male mice in our experiments versus 10-wk-old in ref.…”

“…9,12 Autophagy is a lysosome-mediated degradation pathway actively involved in drug addiction. [17][18][19][20] It has been reported that autophagy regulates the axonal and dendritic degeneration of neurons. 21 Both ATG5 (autophagy-related 5) and ATG7 (autophagy-related 7) are required for the maintenance of axonal homeostasis.…”

“…Indeed, chronic morphine treatment induces BECN1 (Beclin 1, autophagy related)-and ATG5-dependent autophagy. 17 Intracerebroventricular pretreatment with the autophagy inhibitor wortmannin or 3-methyladenine significantly attenuates the antinociception from morphine 18 and aggravates morphineinduced memory impairment. 20 Recently, we found that chronic morphine treatment can cause mitochondrial dysfunction and autophagy, and co-administration of melatonin with morphine ameliorates morphine-induced behavioral sensitization and analgesic tolerance.…”

Role of autophagy in the bimodal stage after spinal cord ischemia reperfusion injury in rats

“…(Kabeya et al, 2000). Recently, Beclin 1 has been known as an important autophagy marker and widely used in evaluating the activation of autophagy (Hayashi et al, 2014). In this study, LC3-II significantly increased and peaked at 8 and 72 h in the spinal cords of the I/R group (P < 0.05, Fig.…”

Cocaine-Mediated Autophagy in Astrocytes Involves Sigma 1 Receptor, PI3K, mTOR, Atg5/7, Beclin-1 and Induces Type II Programed Cell Death

“…Several recent studies with other psychostimulants suggest involvement of autophagy in neurotoxicity [30,33]. For example, morphine-mediated autophagy is responsible for the development of morphine antinociceptive tolerance [39] and methamphetamine has been reported to induce cell death via autophagy [40]. This study revealed for the first time that cocaine exposure induces autophagy in SVGA astrocytes through sigma 1 receptor and mTOR, and PI3KIII/Beclin-1 pathways are involved in cocaine-mediated autophagic process.…”