L51. Pharmacology - Pain Pharmacology

• Opioid peptides, drugs targeting opioid receptors, and pain pharmacotherapy is the subject.

Learning Objectives

• Grasp the basic biosynthetic process for opioid peptides and neuropeptides.
• Know the three main opioid receptor types and the primary drug target.
• Understand opioid receptor signaling, its complexity, and opportunities for drug design.
• Learn features of specific opioid drugs.
• Know when to use and avoid opioid drugs for pain treatment.
• Understand multimodal analgesia.

Lecture Outline

• Opioid neurotransmitters are neuropeptides, including their life cycle and comparison to classical neurotransmitters.
• Discuss opioid peptides and receptors, covering discovery and terminology.
• Opium is discussed, with opiates compared to opioids.
• Identification of multiple genes for opioid peptides and receptors.
• Also covered are opioid receptor signaling pathways.
• Discuss exploiting the complexity of opioid receptor signaling mechanisms.
• Receptor variants and biased agonism are covered.
• Receptor heterodimerization.
• Overview of full agonists, partial agonists, antagonists, and clinical uses.
• Efficacy vs potency.
• Specific MOR drugs, including full agonists, partial agonists, and antagonists.
• Addresses using opioids in treating pain, including when to use them and CDC guidelines.
• Multimodal analgesia: what and why.

Opioid Neurotransmitters

• Peptides were first discovered in peripheral tissues, with CNS pathways mapped using immunochemical techniques.
• CNS peptides affect individual neurons and behavior.
• Neuropeptides are derived from prepropeptides via gene transcription, RNA processing, protein translation, and post-translational processing.
• Neuropeptides are packaged in large, dense core vesicles, unlike traditional neurotransmitters in small synaptic vesicles.
• Peptides coexist with nonpeptide transmitters, with independent regulation of release.
• Released neuropeptides act locally or diffuse to distant receptors.
• Most neuropeptide-responsive receptors are metabotropic and serve modulatory roles.
• Neuropeptides and their receptors are targets for new drug discovery.

Opioid Peptides and Receptors

• Opium is from poppy seeds (Papaver somniferum) and used medicinally for over 5,000 years.
• Morphine, the active component of opium, was isolated around 1805.
• Opioid drugs were once called "God's own medicine" because of their many uses.
• The potential for adverse effects and opioid use disorder are a concern.
• Traditionally, morphine, heroin, and codeine from opium were called opiates.
• Now, any substance interacting with opioid receptors is called an opioid.
• It was discovered that opioid drugs interact with brain binding sites.
• The brain synthesizes endogenous opioid-like peptides working through opium-derived drug sites.
• Stimulation of brain regions produces analgesia blocked by an opioid antagonist.
• Gene cloning identified distinct opioid peptide systems encoded by different genes.
• Pharmacological studies suggested multiple opioid receptors.

Opioid Peptide-Encoding Genes

• Three opioid peptide-encoding genes, including preproopiomelanocortin, preproenkephalin, and preprodynorphin are displayed.
• Each gene encodes endogenous opioid peptides with the N-terminal sequence YGGFM/L.
• Each gene has a unique CNS expression pattern, contributing to opioid pharmacology.
• Three cloned opioid receptor genes are the mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR).
• There are additional, less characterized endogenous opioids and receptors.
• Regulation of opioid peptide synthesis, storage, and release has not been amenable to drug development.
• Multiplicity of receptors is important due to engaging different brain circuits and exhibiting selectivity for endogenous opioids and abused drugs.
• MOR has been the main target for opioid analgesics, but DOR and KOR also regulate pain and analgesia.
• MOR agonists produce analgesia, euphoria, and stress coping.
• KOR agonists can produce dysphoria, stress-like responses, and negative affect.
• DOR agonists can reduce anxiety and promote positive affect.
• Efforts to design agonists and antagonists with differing selectivities and efficacies have not yet yielded clinically effective analgesics with diminished rewarding properties.
• New insights into opioid receptor structure and signaling may lead to new drugs.
• Opioid receptors are inhibitory, decreasing calcium influx and potassium efflux via Gẞy signaling.
• Opioid receptors also decrease PKA and downstream phosphorylation via Ga signaling.
• G-protein-independent receptor interactions can lead to receptor internalization, recycling, or degradation.

Opioid Receptor Signaling Mechanisms for Future Drug Development

• Contributing factors to opioid receptor signaling is complexity include alternate splice variants, biased signaling, and receptor dimerization.
• Alternate promoters of the MOR gene can generate receptor proteins with either 6 or 7 transmembrane domains and different functional properties.
• Biased agonism is when the same receptor couples to distinct pathways to varying extents based on the specific ligand bound.
• KOR analgesic effects are associated with G protein signaling, while KOR-linked dysphoria is associated with beta-arrestin signaling.
• Developing new KOR-binding analgesics biased not to induce dysphoria is of interest.
• Opioid receptors can function as heterodimers with other opioid or non-opioid receptors.

Opioid Drugs

• A full agonist elicits a maximal response, while a partial agonist elicits less than this maximal response.
• An antagonist has no intrinsic activity but blocks the effects of partial or full agonists.
• Morphine is a potent analgesic given by many routes of administration.
• Heroin was quickly abandoned as a medicine due to abuse potential and rapid metabolism to morphine.
• Codeine's individual differences in metabolism to morphine underlie its variable effects, leading to declining clinical use.
• Oxycontin led to the recent prescription opioid epidemic.
• Hydrocodone is the most widely prescribed opioid in the US.
• Fentanyl's high potency and short half-life have led to special therapeutic niches, but illicit manufacture has led to record numbers of opioid deaths.
• Methadone is very long-lasting and used for opioid maintenance therapy.
• Buprenorphine is an effective analgesic used to lessen the rewarding properties of abused full agonists.
• Naloxone is used in different formulations to reverse opioid overdose.
• Naltrexone is given preemptively to blunt illicit drug high (i.e., harm reduction).
• Chemically modified versions of naltrexone are used to prevent opioid-induced constipation.

Treatment of Pain

• Opioids are best employed in palliative care or for acute moderate-severe pain.
• Inappropriate use led to the current opioid epidemic.
• The CDC has new guidelines for prescribing opioids, with a free app available.
• Pain is often best treated through multimodal analgesia with combinations of drugs.
• Nonsteroidal anti-inflammatory drugs and NSAID-opioid combination therapy can be effective.
• Currently, roughly 1 in 5 prescriptions for CNS drugs is for pain treatment.