Table 1.

Summary of selected studies on the role of the striatum (mainly NAc) in chronic pain/nociception.

STUDY	SPECIES	BRAIN REGION	METHOD	MODEL/ TREATMENT	FINDINGS
Gear et al., 1999	Rat	NAc, RVM	Stereotaxic injections, JOR (jaw open reflex)	Subdermal injection of capsaicin, paw immersion in hot water Flupentixol Naloxone Muscimol	Painful stimuli may induce analgesia by activating forebrain structures
Tobaldini et al., 2014	Rat	NAc, RVM	Acupuncture	Orofacial formalin test, intraplantar capsaicin, sciatic C-fibers depletion Bicuculline, Naloxone, Mecamylamine	Ascending nociceptive control contributes to the antinociceptive effect of acupuncture.
Miranda et al., 2015	Rat	NAc	Randall–Selitto nociceptive paw- withdrawal test	Capsaicin- induced analgesia, Persistent hyperalgesia (chronic prostaglandin E2 (PGE2) injections into hind paw) Naloxone, intra- NAc morphine antagonist	Pain chronification and chronic pain reduce the duration of capsaicin- induced analgesia, without affecting its dependence on NAc MOP receptor mechanisms.
Kalivas et al., 1995	Rat	NAc (Core/ Shell)	Microdialysis, HPLC Quantification of Dopamine	Footshock	Increase of extracellular dopamine in the NAc- shell immediately after discontinuing footshock. Unaltered dopamine levels in the NAc-core
Martikainen et al., 2015	Human	Ventral striatum	PET scan	Chronic Non- neuropathic Back Pain patients, painful stimulation by intra-muscle saline infusion	Reductions in D2/D3R binding potential in the ventral striatum compared to controls. These reductions were associated with greater positive affect scores and pain tolerance measures.
Budygin et al., 2012	Rat	NAc (core/ shell), dorsal striatum	FSCV (fast- scan-cyclic voltammetry)	Tail pinch	Dorsal striatum / NAc core: increased dopamine release during stimulus application NAc shell: dopamine concentration suppressed throughout stimulation, increased at offset of stimulus application
Becerra et al., 2001	Human	NAc/ Ventral striatum	fMRI	Thermal noxious stimulus	Painful thermal stimulation activates the ventral striatum
Becerra et al., 2013	Human, rat	NAc, ACC	fMRI	Thermal noxious stimulus	Similar NAc and ACC excitation at pain onset and offset in both species
Baliki et al., 2010	Human	NAc, mPFC	fMRI	Thermal noxious stimulus on healthy subjects and chronic back pain patients	Pain offset differentially affects NAc activity in healthy versus CBP subject.
Navratilova et al., 2012	Rat	NAc, VTA	Microdialysis and HPLC Quantification of Dopamine, Brain Microinjection, CPP, Hargreaves test	Hind paw incision (post- surgical pain) Baclofen, flupenthixol, lidocaine, naloxone	Relief of ongoing postsurgical pain produces CPP and activates the mesolimbic dopaminergic circuit
Xie et al., 2014	Rat	NAc	Microdialysis and HPLC Quantification of Dopamine, CPP	Hind paw incision (post- surgical pain),SNL (neuropathic pain) Clonidine, gabapentin, ketorolac, naproxen	Spinal clonidine produced CPP and produced a dose-related increase in net NAc DA release in SNL rats. Gabapentin, increased NAc DA in rats with SNL. Ketorolac or naproxen produced increased NAc DA in animals with incisional but not neuropathic pain.
Navratilova et al., 2015	Rat	NAc, ACC	In Vivo Microdialysis, CPP, Von Frey, Hargreaves test, Intracranial/ intrathecal cannulation	Hind paw incision (post- surgical pain) SNL (neuropathic pain) Flupenthixol, morphine, naloxone, saporin	Morphine into ACC: DA release in the NAc and promotion of CPP. Intrathecal clonidine: DA release in the NAc and promotion of CPP.
Hagelberg et al., 2003a	Human	Striatum	PET	Burning mouth syndrome	Decrease in the D1/D2 ratio may indicate a decline in endogenous dopamine levels in the putamen in burning mouth patients.
Hagelberg et al., 2003b	Human	Striatum	PET	Atypical facial pain	Changes in D2 receptor availability and D1/D2 ratio in the left putamen and the decrease in D1/D2 ratio in patients with atypical facial pain.
Jensen et al., 2003	Human	Ventral striatum	fMRI (combination of 3 studies)	Cutaneous electrical stimulation	The first study to show that mere anticipation of an aversive stimulus activates ventral striatum in humans
Chang et al., 2014	Rat	NAc	fMRI	SNI Intra-Nac lidocaine	The study demonstrated macroscopic (fMRI) and molecular reorganization of NAc and indicated that NAc neuronal activity is necessary for full expression of neuropathic pain-like behaviors.