Table 4.

Primary findings from fMRI studies of acute opioid agonist and antagonist administration in healthy samples

Ref.	HC (N, Fn)	Acute drug	Design/task	Findings
Borras et al. [100]	10, 0F	NALX (4 mg), IV fixed-dose infusion	Noxious thermal stimuli, hand	NALX > Saline: insula, cingulate, lateral prefrontal, pallidum, lingual, fusiform, PHG, OFC, thalamus, caudate, hippocampus
Oertel et al. [98]	16, 8F	ALF (effect site: 25, 50, 75 ng/ml), TCI	Trigeminal pain stimulation, nasal	ALF < NoDrug: insula, amygdala/PHG, putamen
				ALF(neg. linear dose effect): insula, postcentral, ACC, amygdala/PHG, IFG
Upadhyay et al. [90]	24, 0F (12 BUP, 12 APREP)	BUP (0.2 mg/70 kg), IV fixed-dose infusion; APREP (96 mg/70 kg), IV fixed-dose infusion	phMRI; Noxious thermal stimuli, foot	BUP > NoDrug (phMRI): insula, thalamus, striatum, ACC, OFC, midbrain
				BUP > Saline (thermal): thalamus, striatum, ACC, PCC, MiFG
				APREP > NoDrug(phMRI): thalamus, striatum, amygdala, OFC, midbrain
				APREP > Sal (thermal): ACC, OFC, amygdala
Atlas et al. [93]	21, 11F	REM (indiv. calibrated; mean: 0.88 ng/ml), IV fixed-dose infusion	Noxious thermal stimuli, forearm	REM > NoDrug: fusiform, lingual, STG, MiTG, IPL, postcentral
				REM < NoDrug: striatum, insula, ACC, thalamus, amygdala, angular, supramarginal, MiFG
Upadhyay et al. [89]	36, 0F (12 low, 12 high, 12 SL)	BUP (low = 0.1 mg/70 kg; high = 0.2 mg/70 kg), IV fixed-dose infusion; BUP (SL = 2.0 mg), SL tablet	phMRI, resting-state	BUP-Low > saline (thermal): PCC, cingulate, putamen, thalamus
			Noxious thermal stimuli, foot	BUP-High > Saline (thermal): ACC, frontal, parietal, precuneus, PHG, temporal, putamen, thalamus
				BUP-SL > PBO (thermal): ACC, PCC, frontal, parietal, precuneus, temporal, putamen, thalamus
				Putamen connectivity (phMRI/rest):
				BUP-high/BUP-SL < Sal/PBO: insula, thalamus, cingulate, sensorimotor
Gear et al. [94]	13, 0F	NALX (0.4 mg), single IV injection; NALB (5 mg/70 kg), IV fixed-dose infusion	phMRI	NALB + saline > NoDrug: insula, thalamus, caudate, hippocampus, ITG, STG, fusiform
				NALB + saline < NoDrug: MiFG, OFC, postcentral, temporal pole
				NALX + NALB > NoDrug: insula, putamen, lingual
				NALX + NALB < NoDrug: SFG, OFC
Taylor et al. [88]	15,? F	NALX (0.1 mg/kg), single IV injection	Noxious thermal stimuli, forearm	NALX > NALX + TMS: MeFG, IPL, midbrain, medulla
			TMS of left dlPFC	NALX + TMS > Saline + TMS: midbrain, medulla
Gorka et al. [95]	14, 4F	OXY (low = 10 mg, high = 20 mg), oral tablet	Resting-state	dACC connectivity:
				High > PB/Low: OFC, MeFG, MiFG, SFG, IFG, MiTG
				High/low < PBO: insula, putamen
Wardle et al. [91]	14,? F	OXY (low = 10 mg, high = 20 mg) oral tablet	Emotional pictures task (EPT)	EPT: OXY effect: cuneus, postcentral, lingual, fusiform, thalamus
			Emotional face match task (EFMT)	EPT: OXY x Emo interaction: cuneus, STG
				EFMT: OXY effect: lingual;
				EFMT: OXY x Emo interaction: OFC, SFG
Murray et al. [97]	20, 10F	NTX (50 mg) or placebo	Random, BD CO	NTX < PLA (pleasant): dorsal ACC, MFG
			Pleasant and aversive food cues and tastes	NTX > PLA (aversive): amygdala, insula
Chu et al. [92]	10, 0F	Morphine (10 mg/70 kg), IV, followed by	Precipitated withdrawal model, resting state (ALFF)	Naloxone > morphine: gyrus rectus, IFG, MiFG, SFG, fusiform gyrus, temporal gyrus, caudate, putamen, pregenual cingulate, cerebellum
		Naloxone (10 mg/70 kg), IV		Naloxone < morphine: pre/post-central gyrus, precuneus, posterior insula, STG, cuneus, occipital lobe
Robinson et al. [99]	21, 11F	REM (indiv. calibrated; mean: 0.88 ng/ml), IV fixed-dose infusion	Noxious thermal stimuli, forearm	REM > NoDrug (pain network): lower ACC-insula coupling, lower within ACC and greater within insula connectivity
				ReEM > NoDrug (frontoparietal network): greater frontal-parietal coupling, lower within frontal and within parietal connectivity
Hayen et al. [96]	19, 10F	REM (effect site: 0.7 ng/ml), IV TCI	Resistive inspiratory breathlessness	REM < Sal: insula, ACC, SMA, sensorimotor, thalamus, supramarginal

N total sample size, F_n number of female participants, Ref. reference, HC healthy control, F female, BUP buprenorphine, APREP aprepitant, SL sublingual, NTX naltrexone, Random, BD, CO randomized, double-blind, cross-over, NALX naloxone, IV intravenous, NALB nalbuphine, phMRI pharmacological magnetic resonance imaging, TMS trans magnetic stimulation, dlPFC dorsolateral prefrontal cortex, PHG parahippocampal gyrus, OFC orbitofrontal cortex, ITG inferior temporal gyrus, STG superior temporal gyrus, MiFG middle frontal gyrus, SFG superior frontal gyrus, MeFG medial frontal gyrus, IPL inferior parietal lobule, ACC anterior cingulate cortex, PCC posterior cingulate cortex, PBO placebo, ? not reported