Jiangsu Province Key Laboratory of Anaesthesiology, Xuzhou Medical University, Xuzhou, PR China.
Department of Anesthesiology, Xuzhou Municipal Hospital Affiliated with Xuzhou Medical University, Xuzhou, PR China.
J Psychopharmacol. 2021 May;35(5):591-605. doi: 10.1177/0269881120985183. Epub 2021 Mar 21.
Long-term morphine use is associated with serious side effects, such as morphine-induced hyperalgesia and analgesic tolerance. Previous investigations have documented the association between dopamine (DA) neurons in the ventral tegmental area (VTA) and pain. However, whether VTA DA neurons are implicated in morphine-induced hyperalgesia and analgesic tolerance remains elusive.
Initially, we observed behavioural effects of lidocaine administration into VTA or ablation of VTA DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance. Subsequently, c-Fos expression in nucleus accumbens (NAc) shell-projecting and medial prefrontal cortex (mPFC)-projecting VTA DA neurons after chronic morphine treatment was respectively investigated. Afterwards, the effects of chemogenetic manipulation of NAc shell-projecting or mPFC-projecting DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance were observed. Additionally, effects of chemogenetic manipulation of VTA GABA neurons on c-Fos expression in VTA DA neurons were investigated.
Lidocaine injection into VTA relieved established hyperalgesia and anti-nociceptive tolerance whereas ablation of VTA DA neurons prevented the development of morphine-induced hyperalgesia and anti-nociceptive tolerance. Chronic morphine treatment increased c-Fos expression in NAc shell-projecting DA neurons, rather than in mPFC-projecting DA neurons. Chemogenetic manipulation of NAc shell-projecting DA neurons had influence on morphine-induced hyperalgesia and tolerance. However, chemogenetic manipulation of mPFC-projecting DA neurons had no significant effects on morphine-induced hyperalgesia and anti-nociceptive tolerance. Chemogenetic manipulation of VTA GABA neurons affected the c-Fos expression in VTA DA neurons.
These findings revealed the involvement of NAc shell-projecting VTA DA neurons in morphine-induced hyperalgesia and anti-nociceptive tolerance, and may shed new light on the clinical management of morphine-induced hyperalgesia and analgesic tolerance.
This study demonstrated that NAc shell-projecting DA neurons rather than mPFC-projecting DA neurons in the VTA were implicated in morphine-induced hyperalgesia and anti-nociceptive tolerance. Our findings may pave the way for the discovery of novel therapies for morphine-induced hyperalgesia and analgesic tolerance.
长期使用吗啡会导致严重的副作用，如吗啡诱导的痛觉过敏和镇痛耐受。先前的研究已经证明了腹侧被盖区（VTA）中的多巴胺（DA）神经元与疼痛之间的关联。然而，VTA DA 神经元是否参与吗啡诱导的痛觉过敏和镇痛耐受仍然难以捉摸。
最初，我们观察了将利多卡因注入 VTA 或破坏 VTA DA 神经元对吗啡诱导的痛觉过敏和抗伤害性耐受的行为学影响。随后，分别研究了慢性吗啡处理后 VTA 中壳投射和内侧前额叶皮质（mPFC）投射 DA 神经元中 c-Fos 的表达。随后，观察了 VTA 中 GABA 神经元的化学遗传操作对吗啡诱导的痛觉过敏和抗伤害性耐受的影响。此外，还研究了 VTA GABA 神经元的化学遗传操作对 VTA DA 神经元中 c-Fos 表达的影响。
VTA 内利多卡因注射缓解了已建立的痛觉过敏和抗伤害性耐受，而 VTA DA 神经元的破坏则阻止了吗啡诱导的痛觉过敏和抗伤害性耐受的发展。慢性吗啡处理增加了壳投射 DA 神经元中 c-Fos 的表达，而不是 mPFC 投射 DA 神经元中 c-Fos 的表达。VTA 中 GABA 神经元的化学遗传操作影响了 VTA DA 神经元中 c-Fos 的表达。
这些发现揭示了 VTA 中壳投射 DA 神经元在吗啡诱导的痛觉过敏和抗伤害性耐受中的作用，这可能为吗啡诱导的痛觉过敏和镇痛耐受的临床管理提供新的思路。
本研究表明，VTA 中的壳投射 DA 神经元而不是 mPFC 投射 DA 神经元参与了吗啡诱导的痛觉过敏和抗伤害性耐受。我们的发现可能为发现治疗吗啡诱导的痛觉过敏和镇痛耐受的新疗法铺平道路。
