Lack of Specific Involvement of (+)-Naloxone and (+)-Naltrexone on the Reinforcing and Neurochemical Effects of Cocaine and Opioids

Abstract

Effective medications for drug abuse remain a largely unmet goal in biomedical science. Recently, the (+)-enantiomers of naloxone and naltrexone, TLR4 antagonists, have been reported to attenuate preclinical indicators of both opioid and stimulant abuse. To further examine the potential of these compounds as drug-abuse treatments, we extended the previous assessments to include a wider range of doses and procedures. We report the assessment of (+)-naloxone and (+)-naltrexone on the acute dopaminergic effects of cocaine and heroin determined by in vivo microdialysis, on the reinforcing effects of cocaine and the opioid agonist, remifentanil, tested under intravenous self-administration procedures, as well as the subjective effects of cocaine determined by discriminative-stimulus effects in rats. Pretreatments with (+)-naloxone or (+)-naltrexone did not attenuate, and under certain conditions enhanced the stimulation of dopamine levels produced by cocaine or heroin in the nucleus accumbens shell. Furthermore, although an attenuation of either cocaine or remifentanil self-administration was obtained at the highest doses of (+)-naloxone and (+)-naltrexone, those doses also attenuated rates of food-maintained behaviors, indicating a lack of selectivity of TLR4 antagonist effects for behaviors reinforced with drug injections. Drug-discrimination studies failed to demonstrate a significant interaction of (+)-naloxone with subjective effects of cocaine. The present studies demonstrate that under a wide range of doses and experimental conditions, the TLR4 antagonists, (+)-naloxone and (+)-naltrexone, did not specifically block neurochemical or behavioral abuse-related effects of cocaine or opioid agonists.

Lack of Effects of Toll-Like Receptor 4 Antagonists on the Reinforcing Effects of Cocaine and Remifentanil

“…Tanda and his colleagues further assessed specificity of the blocking effects of the TLR4 antagonists on self-administration of remifentanil or cocaine [5]. Consistent with the results from the two earlier studies [3,4], both (+)-naloxone and (+)-naltrexone dose-dependently produced an insurmountable antagonism against self-administration of remifentanil or cocaine.…”

“…These findings suggested a "novel" TLR4-mediated mechanism underlying the reinforcing effects of drugs of abuse across pharmacological classes. A more recent study [5] has, however, indicated that the TLR4 hypothesis is less viable.…”

“…The more recent results by Tanda et al [5] indicate the following message: 1) There is no specific preclinical efficacy of TLR4 antagonists (+)-naloxone and (+)-naltrexone for self-administration of cocaine and remifentanil. Thus, the TLR4 hypothesis is less viable to develop medications for drug abuse; 2) It is important to assess pharmacological specificity using food-reinforced responding as successfully employed in previous studies [5][6][7][8][9].…”

“…Thus, the TLR4 hypothesis is less viable to develop medications for drug abuse; 2) It is important to assess pharmacological specificity using food-reinforced responding as successfully employed in previous studies [5][6][7][8][9].…”

“…These findings suggested a "novel" TLR4-mediated mechanism underlying the reinforcing effects of drugs of abuse across pharmacological classes. A more recent study [5] has, however, indicated that the TLR4 hypothesis is less viable.Tanda and his colleagues further assessed specificity of the blocking effects of the TLR4 antagonists on self-administration of remifentanil or cocaine [5]. Consistent with the results from the two earlier studies [3,4], both (+)-naloxone and (+)-naltrexone dose-dependently produced an insurmountable antagonism against self-administration of remifentanil or cocaine.…”