“…Hence a sizable literature on blockade of LPS effects by naloxone and naltrexone makes no mention of TLR4, as it had not yet been discovered. The evidence of naloxone/naltrexone blockade of LPS effects is now quite far-reaching including excitatory post-synaptic potentials [22], seizures [23, 24], microglial activation [25–27], proinflammatory cytokines [25, 28], nitric oxide and superoxide [29, 30], neurotoxicity and neurodegeneration [31–34], hepatitis [35], septic shock [36, 37], hormone release [38], fever [39], pain [40], reduction in morphine analgesia [41, 42], and so on. Even when (+)-isomers of naloxone and naltrexone are employed to prevent possible influence of opioid receptors, there is suppression of LPS-induced proinflammatory responses [34, 43], LPS-induced excitotoxic death of dopamine neurons [33, 34]; suppression of neuropathic pain [12, 44]; potentiation of opioid analgesia [10, 45]); and decreased opioid-induced withdrawal, tolerance, hyperalgesia and constipation [2, 7, 10, 40].…”