Involvement of mesolimbic dopaminergic network in neuropathic pain relief by treadmill exercise

Abstract

BackgroundExercise alleviates pain and it is a central component of treatment strategy for chronic pain in clinical setting. However, little is known about mechanism of this exercise-induced hypoalgesia. The mesolimbic dopaminergic network plays a role in positive emotions to rewards including motivation and pleasure. Pain negatively modulates these emotions, but appropriate exercise is considered to activate the dopaminergic network. We investigated possible involvement of this network as a mechanism of exercise-induced hypoalgesia.MethodsIn the present study, we developed a protocol of treadmill exercise, which was able to recover pain threshold under partial sciatic nerve ligation in mice, and investigated involvement of the dopaminergic reward network in exercise-induced hypoalgesia. To temporally suppress a neural activation during exercise, a genetically modified inhibitory G-protein-coupled receptor, hM4Di, was specifically expressed on dopaminergic pathway from the ventral tegmental area to the nucleus accumbens.ResultsThe chemogenetic-specific neural suppression by Gi-DREADD system dramatically offset the effect of exercise-induced hypoalgesia in transgenic mice with hM4Di expressed on the ventral tegmental area dopamine neurons. Additionally, anti-exercise-induced hypoalgesia effect was significantly observed under the suppression of neurons projecting out of the ventral tegmental area to the nucleus accumbens as well.ConclusionOur findings suggest that the dopaminergic pathway from the ventral tegmental area to the nucleus accumbens is involved in the anti-nociception under low-intensity exercise under a neuropathic pain-like state.

Relief of Pain-Depressed Behavior in Rats by Activation of D1-Like Dopamine Receptors

“…For example, exercise is often a part of multimodal pain treatment (Canadian Agency for Drugs and Technologies in Health, 2016; Laubenstein and Beissner, 2016), but behavioral impairment produced by either pain or sedative medications may interfere with patient participation. The benefits of exercise in pain treatment appear to involve mesolimbic dopaminergic mechanisms (Wakaizumi et al, 2016), and drugs such as methylphenidate or SKF82958 may be useful as adjuncts to physical therapy.…”

Analgesic Mechanisms of Antidepressants for Neuropathic Pain

“…Dopaminergic neurons in the ventral tegmental area (A10) release dopamine in the nucleus accumbens and enhance analgesic activity through D2-like receptors [ 77 , 78 , 79 ]. A previous study demonstrated that duloxetine (25 mg/kg orally) increases dopamine in the nucleus accumbens, but amitriptyline and maprotiline (both 50 mg/kg orally) do not have this effect [ 80 ].…”

The Impact of Exercise in Rodent Models of Chronic Pain

“…Considering that the forced running studies discussed here generally employed little or no pre-training prior to relatively high exercise intensities, it is somewhat surprising that rodents with painful hind paw injuries were able to complete the studies. Indeed, a number of studies reported that some rodents were excluded due to stress or refusal to run [ 90 , 91 •, 92 , 96 , 106 , 107 ], while another reported that some mice discontinued running at the 12 m/min velocity during the therapeutic exercise phase [ 95 ]. Moreover, a number of studies indicated that electric shocks or physical encouragements were required to ensure continued running [ 90 , 91 •, 92 – 94 , 108 • , 109 – 113 , 114 ••, 115 – 117 ].…”