Fentanyl rose to prominence as an alternative analgesic to morphine nearly 50 years ago; today, fentanyl has re-emerged as a dangerous recreational substance. The increased potency and analgesic effect of fentanyl are advantageous in the treatment of pain but are also responsible for the rise in unintentional opioid overdose deaths. In response to this crisis, fentanyl, its analogues, and even precursors are under heightened regulatory scrutiny. Despite this controversial history, derivatization of fentanyl has resulted in numerous synthetic analogues that provide valuable insights into opioid receptor binding and signaling events. In this review, the impact of fentanyl on chemical neuroscience is shown through its synthesis and properties, manufacturing, metabolism, pharmacology, approved and off-label indications, adverse effects, and the responsibility it has in the opioid epidemic.

In this proof-of-concept study, the efficacy of a medium-pressure UV (MPUV) lamp source to reduce the concentrations of aflatoxin B, aflatoxin B, and aflatoxin G (AFB AFB, and AFG) in pure water is investigated. Irradiation experiments were conducted using a collimated beam system operating between 200 to 360 nm. The optical absorbance of the solution and the irradiance of the lamp are considered in calculating the average fluence rate. Based on these factors, the UV dose was quantified as a product of average fluence rate and treatment time. Known concentrations of aflatoxins were spiked in water and irradiated at UV doses ranging from 0, 1.22, 2.44, 3.66, and 4.88 J cm. The concentration of aflatoxins was determined by HPLC with fluorescence detection. LC-MS/MS product ion scans were used to identify and semi-quantify degraded products of AFB, AFB, and AFG. It was observed that UV irradiation significantly reduced aflatoxins in pure water (p < 0.05). Irradiation doses of 4.88 J cm reduced concentrations 67.22% for AFG, 29.77% for AFB, and 98.25% for AFB (p < 0.05). Using this technique, an overall reduction of total aflatoxin content of ≈95% (p < 0.05) was achieved. We hypothesize that the formation of ˙OH radicals initiated by UV light may have caused photolysis of AFB, AFB, and AFG molecules. In cell culture studies, our results demonstrated that the increase of UV dosage decreased the aflatoxin-induced cytotoxicity in HepG cells. Therefore, our research finding suggests that UV irradiation can be used as an effective technique for the reduction of aflatoxins.

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Opioid overdose is one of the leading causes of death in the United States in people under 50 years, which has resulted in a decline in life expectancy in the United States. Thus, there is a need for an alternative to prescription mu‐opioid agonists for pain treatment. Delta (9)‐tetrahydrocannabinol (THC), a cannabinoid (CB) agonist, has been shown to produce antinociceptive effects albeit less effectively than mu‐opioid receptor agonists. Sigma1 receptor (σ1R) antagonists in combination with THC may provide a viable and safe pharmacological alternative to prescription opioids for pain treatment. The present study compared the pharmacological effects of the σ1R antagonist CM304 alone and in combination with THC in Sprague Dawley rats. Hotplate latency was determined at 52°C followed by rectal temperature measurement and the drugs were administered intravenously (i.v.) and in cumulative doses every 5 min. THC dose‐dependently increased maximum possible effects (MPEs) up to 84% which were reversed by 10 mg/kg rimonabant (cannabinoid CB1 receptor antagonist). CM304 alone up to a dose of 10 mg/kg did not produce significant antinociceptive or hypothermic effects, but CM304 (1.0 and 3.2 mg/kg, i.v.) dose‐dependently left‐shifted the dose‐effect functions of the antinociceptive (7.3‐fold at 3.2 mg/kg CM304) and hypothermic effects of THC. In rats discriminating 3.2 mg/kg THC i.p. from vehicle under a fixed ratio (FR) 10 schedule of food delivery, the cannabinoid CB1 receptor agonist CP55,940 fully substituted for THC, whereas CM304 i.p. produced a maximum of 27 % THC‐lever responding at 17.8 mg/kg. CM304, at doses of 32 and 56 mg/kg, decreased response rate to 24 and 9 %, respectively. No dose of BD1063 (σ1R antagonist), rimonabant, SR144528 (cannabinoid CB2 receptor antagonist), morphine (μ‐opioid receptor agonist), or naltrexone (opioid antagonist) produced greater than 30% THC‐lever responding. Pretreatment with rimonabant (1.78 mg/kg) produced a rightward shift in the dose effect curve of THC (4.5‐fold) and CP55940 (4.5‐fold) while pretreatment with CM304, BD1063, SR144528, and naltrexone had no significant effect on the dose effect curve of THC. The present results may support the development of a σ1R antagonist as an adjunct to cannabinoids for treatment of acute pain without enhancing an undesirable side effect of THC. Support or Funding Information This work was supported by National Institute on Drug Abuse grants DA23205 and DA48353.

There is an overdose epidemic associated with the use of illicitly manufactured as well as prescription mu‐opioid receptor agonists. Sigma1 receptor (σ1R) antagonists in combination with other drugs may provide a viable, safer pharmacological option than opioids alone for treating pain. The present study compared pharmacological effects of the σ1R antagonist CM304 alone and in combination with high (fentanyl and morphine) and low (buprenorphine) efficacy opioid agonists and the cannabinoid CB (CP55,940 and THC) receptor agonists in C57BL/6J mice. Rectal temperature, tail withdrawal latency (10‐seconds cutoff) from warm water of various temperatures (45°C, 50°C and 55°C) and counts of unhabituated locomotor activity were measured in this order. Basal latency for tail withdrawal systematically decreased from 10 seconds at 45°C to 1.3 seconds at 55°C. Morphine, fentanyl and buprenorphine dose‐dependently increased maximum possible effects (MPEs) up to 100% at 55°C (ED50 values: 7.50, 0.068, and 1.13 mg/kg, respectively), whereas CP55,940 and THC were less effective at 55°C (Emax values: 56.6% and 58.2%, respectively). CM304 (56 mg/kg, i.p.) produced an upward shift in the CP55,940 dose‐effect function such that 100% MPE was achieved at 3.2 mg/kg CP55,940, while CM304 (56 mg/kg) produced a 3‐fold leftward shift in the dose‐effect curve of THC. On the other hand, CM304 did not enhance the antinociceptive effects of morphine and fentanyl but enhanced the effects of buprenorphine. In contrast to tail withdrawal latency, there were no consistent effects of CM304 on cannabinoid‐induced decreases in rectal temperature or locomotor activity. The present results may support the development of a σ1R antagonist as an adjunct to cannabinoid and low efficacy μ‐opioid receptor agonists for the treatment of acute pain. Support or Funding Information This work was supported by National Institute on Drug Abuse grants DA23205 and DA48353.