Activation of ventral tegmental area dopaminergic neurons reverses pathological allodynia resulting from nerve injury or bone cancer.
Chronic pain induced by nerve damage due to trauma or invasion of cancer to the bone elicits severe ongoing pain as well as hyperalgesia and allodynia likely reflecting adaptive changes within central circuits that amplify nociceptive signals. The present study explored the possible contribution of the mesolimbic dopaminergic circuit in promoting allodynia related to neuropathic and cancer pain. Mice with ligation of the sciatic nerve or treated with intrafemoral osteosarcoma cells showed allodynia to a thermal stimulus applied to the paw on the injured side. Patch clamp electrophysiology revealed that the intrinsic neuronal excitability of ventral tegmental area (VTA) dopamine neurons projecting to the nucleus accumbens (N.Acc.) was significantly reduced in those mice. We used tyrosine hydroxylase (TH)-cre mice that were microinjected with adeno-associated virus (AAV) to express channelrhodopsin-2 (ChR2) to allow optogenetic stimulation of VTA dopaminergic neurons in the VTA or in their N.Acc. terminals. Optogenetic activation of these cells produced a significant but transient anti-allodynic effect in nerve injured or tumor-bearing mice without increasing response thresholds to thermal stimulation in sham-operated animals. Suppressed activity of mesolimbic dopaminergic neurons is likely to contribute to decreased inhibition of N.Acc. output neurons and to neuropathic or cancer pain-induced allodynia suggesting strategies for modulation of pathological pain states.
['Watanabe|Moe|M|', 'Narita|Michiko|M|', 'Hamada|Yusuke|Y|', 'Yamashita|Akira|A|', 'Tamura|Hideki|H|', 'Ikegami|Daigo|D|', 'Kondo|Takashige|T|', 'Shinzato|Tatsuto|T|', 'Shimizu|Takatsune|T|', 'Fukuchi|Yumi|Y|', 'Muto|Akihiro|A|', 'Okano|Hideyuki|H|', 'Yamanaka|Akihiro|A|', 'Tawfik|Vivianne L|VL|', 'Kuzumaki|Naoko|N|', 'Navratilova|Edita|E|', 'Porreca|Frank|F|', 'Narita|Minoru|M|']
D000818:Animals D001859:Bone Neoplasms D000072716:Cancer Pain D045744:Cell Line, Tumor D059290:Dopaminergic Neurons D006930:Hyperalgesia D008026:Ligation D008297:Male D008810:Mice, Inbred C57BL D009437:Neuralgia D009714:Nucleus Accumbens D012584:Sciatic Nerve D017557:Ventral Tegmental Area
cancer pain dopamine optogenetics mesolimbic dopaminergic neurons Neuropathic pain