Analysis of natural product regulation of opioid receptors in the treatment of human disease.

Opioid receptors (ORs), µOR, δOR, κOR and ORL1 mediate numerous signalling cascades, most importantly, through the modulation of ion channels. Research demonstrates the role of OR mediated signal transduction in treating pain, cancer, neurodegenerative disorders and cardiac insults. Yet, the primary application of drugs that modulate ORs is analgesia. Current opioids like morphine that are mainly µOR orthosteric agonists attract many undesirable side-effects (constipation, urinary retention, respiratory depression and hypotension) and the existing modus operandi against these is the inclusion of a µOR antagonist (for example, naloxone) which itself produces side-effects. As such, there is a current thrust to delineate the anti-nociceptive pathways mediated by ORs from the pathways involved in their induction of debilitating side-effects, in order to develop enhanced lead molecules. This review discusses the effects of natural products on the OR-induced signalling cascades and compares these to current synthetic leads and drugs. Important to these discussions is the complexity of OR signalling which involves OR trafficking, de- and re-sensitization, homo- and hetero-dimerization, the type of ligand binding (agonist, antagonist, reverse antagonist, orthosteric and allosteric agonist and antagonist in the context of biased agonism) and reasons for dysregulation that primarily occur because of inter-individual variations. Our current understanding of the different forms of ORs has expanded, thus introducing the concept of allosterism, which is also discussed. The authors present possible combination therapies to be explored towards developing the 'Holy Grail' of analgesics, for example, ignavine, the natural µOR positive allosteric modulator (PAM) with codeine and the natural fascaplysin, a balanced agonist with fentanyl. There remain many gaps in natural products research on ORs, more so on ORL1 and δ- and κ receptors. Furthermore, additional exploration of ORs' modulation is needed for ameliorating other associated disease conditions of global concern.

An assessment of the in vivo effects of intravenous lipid emulsion on blood drug concentration and haemodynamics following oro-gastric amitriptyline overdose.

BACKGROUND: Overdose with lipophilic drugs, such as amitriptyline, may cause cardiotoxicity in overdose. Severe poisoning can be resistant to traditional treatments. Intravenous lipid emulsion (ILE) has been recommended as a novel therapy for the treatment of such overdoses; however, a little is known about the effects of ILE-infusion on drug concentration and haemodynamics in the early/absorptive phase after oral poisoning. METHOD: Thirty minutes after oro-gastric administration of amitriptyline (70 mg/kg), either 20% intravenous lipid emulsion (ILE), 8.4% sodium bicarbonate or Hartmann's solution was infused to anaesthetized and ventilated rodents (n = 10 per group). Heart rate, blood pressure, cutaneous ECG - QRS interval duration (QRS-d), and survival were serially recorded over 120 min. Blood drug concentrations were also collected during this period. Continuous variables were compared using one-way ANOVA. RESULTS: ILE infusion significantly decreased the survival compared to other treatments (10% ILE vs 70% bicarbonate vs 70% Hartmann's solution, p = 0.005). There was a gradual prolongation of QRS-d and fall in blood pressure over time compared to baseline (T0) measurement for both ILE and Hartmann's solution treatments. This was associated with significantly increased blood AMI concentration with ILE treatment at T60, T90 and T120 min to the other treatments (p < 0.02). CONCLUSION: Administration of ILE early after oral amitriptyline overdose resulted in worse survival and no improvement in haemodynamics. In addition, blood amitriptyline concentrations were higher in the ILE-treated group. This suggests that either drug absorption from the gastrointestinal-tract was facilitated or drug redistribution was retarded when ILE was given early after oral poisoning.