Table 1.

The effect of endogenous opioid, exogenous opioids and naloxone on PTSD and associated pain

Human/animal models	Subtype	Endogenous opioid effect	Exogenous opioid (agonist) effect	Exogenous opioid dosage	Naloxone/Naltrexone (antagonist) effect	Naloxone dosage	Reference
PTSD in human and associated pain			In survival of war trauma, morphine injection for pain reliving reduced the PTSD symptoms like intrusive thoughts (non-dose dependent)	Morphine injected in dosages of 2,5, 10 and 20 mg/kg (i.v.)			Holbrook et al. [9]
					Naloxone has improved the depersonalization symptoms of PTSD	1.6, 4 and 10 mg (i.v.)	Nuller et al. [40]
					Naloxone have reduced the pain threshold and increased the PTSD and associated pain in combat related-patient	1 mg/mL (i.v.)	Pitman et al. [53]
			Chronic morphine injection implicated in pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) elevation that leads to hyperalgesia and allodynia.	5 mg/mL intrathecal			Johnston et al. [113]
			Depression and anxiety symptoms of PTSD occurred via these cytokines function
					Naltrexone coupling with SSRI antidepressant is good for modulating PTSD syndrome	50 mg	Petrakis et al. [14]
Animal model of PTSD and associated pain	Repeated restraint stress	Endogenous opioid in rained cats modulated the LC firing activity only under stress conditions			Naloxone increased the firing rate of LC that is important in arousal and anxiety state	1 mg/kg (i.v.)	Abercrombie and Jacobs [41]
Animal model of PTSD and related pain		Immediately endogenous opioids will be activated after traumatic events like swim stress in mice and it will be reducing the pain. It is confirmed by beta-endorphin genes knockdown					Parikh et al. [127]
	Forced to swim stress		Reduced the time of immobility in mice as an index of fear	5 mg/kg (s.c.)	Increased the time of immobility by blocking the anti-immobility effect of morphine	1 mg/kg (i.p.)	Zomkowski et al. [47]
	Continuous cold water swimming	Analgesia happened but doesn’t have opioid origins			Analgesia is reversed by high dosage of naloxone (this effect is independent of opioid system)	20 mg/kg	Girardot and Holloway [54]
	Intermittent cold water swimming	Analgesia happened by endogenous opioid system			Analgesia is reversed by a common dosage of naltrexone	14 mg/kg
Animal model ofPTSD and associated pain	Escapable/inescapable shock		After inescapable shock, but not escapable, morphine injection 24 hours after shock reduced the pain	1 mg/kg (s.c.)	Naltrexone decreased the pain threshold in inescapable shock by reversing the analgesic effect but it reduced the emotional numbing	7 and 14 mg/kg (s.c.)	Hyson et al. [18]
	Foot shock stress	Inescapable intermittent foot shock, for 30 minute induced analgesia by endogenous opioid system			Naloxone reversed this analgesia		Menendez et al., [55] Lewis et al. [56]
		A long time foot shock stress, did not leads to analgesia and this phenomena is independent of glucocorticoid or endogenous opioid activity (have a nonopioid mechanism)				10 mg/kg (s.c.)
Animal model ofPTSD and associated pain	Inescapable tail-shock		Morphine injection increased the BDNF. These factor implicated in start ofPTSD symptoms and arousal responses	5, 10, and 15 mg/kg			Vargas-Perez et al., [12] Zhang et al. [128]
	Predator stress	Stress leads to analgesia by opioid endogenous system and by non-opioid mechanism					Hendrie [57]
	Social defeat stress	Stress induced analgesia	Morphine injection, before stress have reduced the analgesic effect in tail flick test but when injected after stress, the pain threshold increased	5 mg/kg (i.p.)	Naloxone injection after stress or 30 min after morphine injection, reduced the withdrawal jumping and decreased the pain threshold	1 μg and 10 μg intracerebral, 10 mg/kg (i.p.)	Miczek et al. [52]
	SPS stress		Morphine injection in SPS rats 48 hours after stress reduced the fear learning and freezing behavior	7.5 and 15 mg/kg (s.c.)			Szczytkowski-Thomson et al. [11]

PTSD: post-traumatic stress disorder, SSRI: selective serotonin reuptake inhibitor, LC: locus coeruleus, SPS: single-prolong stress, BDNF: brain-derived neurotrophic factor, IL-1β: interleukin-1β, IL-6: interleukin-6, TNF-α: tumor necrosis factor-α