The Pharmacology of Opioids (DRAFT)

This chapter focuses on the attributes of and component medications within the class of opioids, emphasizing kinetics, dynamics, and therapeutic and adverse effects. To help patients make informed decisions about opioid use, the clinicians prescribing these medications must be able to explain when opioids are likely to help and when they are likely to do harm. Subclasses of opioids include phenanthrenes, benzomorphans, phenylpiperidines, and diphenylheptanes; examples are given of each, with respective utilities and limitations. A discussion then follows of pharmacodynamics, pharmacokinetics, opioid receptor affinity, metabolism, and drug interactions. Tables and figures amplifying the text include: opioid class by synthetic method (Table 8.1); common physiological effects by opioid receptor subtypes (Table 8.2); opioid activity (Table 8.3); and a listing of figures and tables located in Appendix B (opioid receptor affinity, respiratory depression with opioids, adverse effects, metabolism, pharmacogenetics, extended release/long-acting opioids, abuse deterrent formulations). A text box provides supplemental resources.

Antinociceptive Activity of Methanolic Extract ofClinacanthus nutansLeaves: Possible Mechanisms of Action Involved

Methanolic extract ofClinacanthus nutansLindau leaves (MECN) has been proven to possess antinociceptive activity that works via the opioid and NO-dependent/cGMP-independent pathways. In the present study, we aimed to further determine the possible mechanisms of antinociception of MECN using various nociceptive assays. The antinociceptive activity of MECN was (i) tested against capsaicin-, glutamate-, phorbol 12-myristate 13-acetate-, bradykinin-induced nociception model; (ii) prechallenged against selective antagonist of opioid receptor subtypes (β-funaltrexamine, naltrindole, and nor-binaltorphimine); (iii) prechallenged against antagonist of nonopioid systems, namely,α2-noradrenergic (yohimbine),β-adrenergic (pindolol), adenosinergic (caffeine), dopaminergic (haloperidol), and cholinergic (atropine) receptors; (iv) prechallenged with inhibitors of various potassium channels (glibenclamide, apamin, charybdotoxin, and tetraethylammonium chloride). The results demonstrated that the orally administered MECN (100, 250, and 500 mg/kg) significantly (p<0.05) reversed the nociceptive effect of all models in a dose-dependent manner. Moreover, the antinociceptive activity of 500 mg/kg MECN was significantly (p<0.05) inhibited by (i) antagonists of μ-,δ-, andκ-opioid receptors; (ii) antagonists ofα2-noradrenergic, β-adrenergic, adenosinergic, dopaminergic, and cholinergic receptors; and (iii) blockers of different K+channels (voltage-activated-, Ca2+-activated, and ATP-sensitive-K+channels, resp.). In conclusion, MECN-induced antinociception involves modulation of protein kinase C-, bradykinin-, TRVP1 receptors-, and glutamatergic-signaling pathways; opioidergic,α2-noradrenergic,β-adrenergic, adenosinergic, dopaminergic, and cholinergic receptors; and nonopioidergic receptors as well as the opening of various K+channels. The antinociceptive activity could be associated with the presence of several flavonoid-based bioactive compounds and their synergistic action with nonvolatile bioactive compounds.

Endogenous central amygdala mu-opioid receptor signaling promotes sodium appetite in mice

Due to the importance of dietary sodium and its paucity within many inland environments, terrestrial animals have evolved an instinctive sodium appetite that is commensurate with sodium deficiency. Despite a well-established role for central opioid signaling in sodium appetite, the endogenous influence of specific opioid receptor subtypes within distinct brain regions remains to be elucidated. Using selective pharmacological antagonists of opioid receptor subtypes, we reveal that endogenous mu-opioid receptor (MOR) signaling strongly drives sodium appetite in sodium-depleted mice, whereas a role for kappa (KOR) and delta (DOR) opioid receptor signaling was not detected, at least in sodium-depleted mice. Fos immunohistochemistry revealed discrete regions of the mouse brain displaying an increased number of activated neurons during sodium gratification: the rostral portion of the nucleus of the solitary tract (rNTS), the lateral parabrachial nucleus (LPB), and the central amygdala (CeA). The CeA was subsequently targeted with bilateral infusions of the MOR antagonist naloxonazine, which significantly reduced sodium appetite in mice. The CeA is therefore identified as a key node in the circuit that contributes to sodium appetite. Moreover, endogenous opioids, acting via MOR, within the CeA promote this form of appetitive behavior.

Opiate Pharmacology and Relief of Pain

Opioids remain the mainstay of severe pain management in patients with cancer. The hallmark of pain management is individualization of therapy. Although almost all clinically used drugs act through mu opioid receptors, they display subtle but important differences pharmacologically. Furthermore, not all patients respond equally well to all drugs. Evidence suggests that these variable responses among patients have a biologic basis and are likely to involve both biased agonism and the many mu opioid receptor subtypes that have been cloned.