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AC: adenylyl cyclase

ACTH: corticotropin; formerly adrenocorticotropic hormone

ADH: antidiuretic hormone

COPD: chronic obstructive pulmonary disease

CSF: cerebrospinal fluid

CYP: cytochrome P450

DAMGO: [D-Ala2,MePhe4,Gly(ol)5]enkephalin

EEG: electroencephalogram

FSH: follicle-stimulating hormone

GABA: γ-aminobutyric acid

GI: gastrointestinal

GPCR: G protein-coupled receptor

GRK: GPCR kinase

HPA: hypothalamic-pituitary-adrenal

5HT: serotonin

LH: luteinizing hormone

6-MAM: 6-monoacetylmorphine

MAO: monoamine oxidase

MAPK: mitogen-activated protein kinase

NE: norepinephrine

NMDA: N-methyl-D-aspartate

NOP: nociceptin/orphanin FQ (N/OFQ)

NOPr: NOP receptor

NSAID: nonsteroidal anti-inflammatory drug

PAG: periaqueductal gray

PCA: patient-controlled analgesia

PKC: protein kinase C

POMC: proopiomelanocortin

TM: transmembrane


Pain is a common component of many clinical pathologies, and management of pain is a vital clinical need. Drugs such as morphine and oxycodone acting at opioid receptors remain the mainstay of pain treatment, despite the safety concerns associated with the long-term use of these drugs, which has led to addiction and death from their misuse and the worldwide opioid crisis. Morphine and related drugs exert their pharmacological effects by acting at opioid receptors. Opioid receptors are 7-transmembrane G protein-coupled receptors (GPCRs; see Chapter 3) and comprise a family of four types, the mu (μ), delta (δ), kappa (κ) opioid receptors, which we will refer to as the classical or canonical opioid receptors, and the nociceptin (NOP) receptor (NOPr), which has close structural homology to the classical opioid receptors but distinct ligands and pharmacology. In this chapter, we will use mu, delta, kappa, and NOPr to describe the receptors. The mu-opioid receptor is mainly responsible for the pain-relieving actions and, importantly, also the unwanted effects, of all clinically useful opioid analgesics, which generally mimic the pharmacology of morphine. Consequently, this chapter will focus mainly on this receptor and its ligands and their pharmacology, with some mention of the pharmacology of drugs acting at the delta, kappa, and NOPr receptors.

The original opioid drugs (morphine and codeine) are components of opium, the dried resin from the seed head of the opium poppy, Papaver somniferum. Opium also contains thebaine, which has no opioid activity but serves as a precursor for the synthesis of additional opioid drugs. Also present in opium are papaverine (1%), a smooth muscle relaxant, and noscapine (6%), which has been used as an antitussive. Morphine, codeine, and structurally related compounds found in opium, together with semisynthetic derivatives such as oxycodone that bind to the mu-opioid receptor, are termed opiates. In contrast, an opioid is any agent that binds to the ligand-binding (orthosteric) site of members of the opioid receptor family. Consequently, the term opioid is a broader definition and covers the opiates, fully synthetic drugs, such a methadone and fentanyl, and endogenous opioid peptides, including the enkephalins, endorphins, and dynorphins, which are the naturally occurring neurotransmitters acting at opioid receptors. Opioid drugs are often referred to as narcotic analgesics ...

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