Synaptic potentiation of anterior cingulate cortex contributes to chronic pain of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a multi-system neurodegenerative disorder. Patients with PD often suffer chronic pain. In the present study, we investigated motor, sensory and emotional changes in three different PD mice models. We found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treatment caused significant changes in all measurements. Mechanical hypersensitivity of PD model induced by MPTP peaked at 3 days and persisted for at least 14 days. Using Fos transgenic mice, we found that neurons in the anterior cingulate cortex (ACC) were activated after MPTP treatment. Inhibiting ACC by bilateral microinjection of muscimol significantly reduced mechanical hypersensitivity and anxiety-like responses. By contrast, MPTP induced motor deficit was not affected, indicating ACC activity is mostly responsible for sensory and emotional changes. We also investigated excitatory synaptic transmission and plasticity using brain slices of MPTP treated animals. While L-LTP was blocked or significantly reduced. E-LTP was not significantly affected in slices of MPTP treated animals. LTD induced by repetitive stimulation was not affected. Furthermore, we found that paired-pulse facilitation and spontaneous release of glutamate were also altered in MPTP treated animals, suggesting presynaptic enhancement of excitatory transmission in PD. Our results suggest that ACC synaptic transmission is enhanced in the animal model of PD, and cortical excitation may play important roles in PD related pain and anxiety.

Cortical synaptic mechanism for chronic pain and anxiety in Parkinson’s disease

“…The presynaptic and postsynaptic excitatory transmissions of ACC neurons are enhanced in MPTP-treated mice. [25] The results are similar to ACC plastic changes reported in previous studies in different chronic pain animal models. [28,29] As a novel target for chronic pain, adenylyl cyclase 1 (AC1) has been proved to be essential for the presynaptic enhancement of glutamate release and postsynaptic potentiation.…”

“…[24] Our recent study confirmed that MPTPtreated and 6-OHDA-treated mice exhibited thermal hyperalgesia and mechanical pain hypersensitivity. [25] In studies of anxiety symptom, MPTP-treated mice showed increased anxiety in the marble-burying test, [26] and the 6-OHDA injection also induced anxiety-like behavior in the elevated plus maze. [27] Therefore, we believe that MPTP-induced and 6-OHDAinduced PD models are appropriate models to study the chronic pain and anxiety symptoms of PD patients.…”

“…Our recent study reported that ACC was activated bilaterally in MPTP-treated mice. [ 25 ] By local infusion of muscimol, inactivation of the ACC reversed the chronic pain and anxiety symptoms in MPTP-treated mice, suggesting that ACC activity at least partially contribute to chronic pain and emotional anxiety in PD model mice. Furthermore, the motor impairment in MPTP-treated mice was not affected by ACC microinjection of muscimol, indicating that ACC is relatively selective involved in sensory and emotional functions of PD model mice.…”

Human safety study of a selective neuronal adenylate cyclase 1 inhibitor NB001 which relieves the neuropathic pain and blocks ACC in adult mice

“…Recent studies have also demonstrated the analgesic effect of NB001 on animal models of gouty arthritis, migraine, and Parkinson's disease-related pain. [17][18][19][20] The analgesic effect of NB001 is believed to be produced by inhibiting several central synaptic mechanisms that are critical for chronic pain and related emotional changes. 21 They include the following: cortical postsynaptic long-term potentiation (post-LTP) and presynaptic long-term potentiation (pre-LTP) in the ACC and IC, 5 activation of various immediate early genes, 22,23 upregulation of NMDA receptors 24 after injury, new protein synthesis of AC1 after injury, 15 spinal LTP and serotonin-induced facilitation.…”

Correction to: Synaptic potentiation of anterior cingulate cortex contributes to chronic pain of Parkinson’s disease

“…Following publication of the original article [ 1 ], the authors identified an incorrect paragraph with Chinese text at the end of the ‘Recruitment of synaptic responses is blocked in MPTP-treated mice’ subsection in the ‘Results’. This paragraph has been removed and the original article [ 1 ] has been updated.…”