Review of Neuropeptides, Atypical Neurotransmitters, Pain, Neuroinflammation, Reinforcement & Addiction, and Neurotrophic Factors

Vocabulary flashcards covering key terms and definitions from the lecture notes.

Neuropeptides

Act as neurotransmitters (neuromodulators) and hormones when released directly into the bloodstream.

Prepropeptide

Precursor polypeptide that contains a signal peptide to direct it to the lumen of the ER & appropriate secretory compartment.

Propeptide

Formed after the signal peptide is cleaved off the prepropeptide; transferred to the Golgi complex and packaged in large dense core vesicles (LDCVs).

Proteolytic Cleavage

Process by which neuropeptides may be produced. For example, proopiomelanocortin (POMC) is a propeptide that is cleaved by enzymes to form a number of bioactive peptides.

Proopiomelanocortin (POMC)

A propeptide that is cleaved by enzymes to form a number of bioactive peptides, including ACTH and β-endorphin.

Adrenocorticotropic hormone (ACTH)

A peptide hormone released from the anterior pituitary gland that binds to melanocortin receptors (MC2) and signals the adrenal gland to synthesize and release cortisol.

Beta-endorphin

An opioid peptide that has multiple effects, including modulation of pain processing.

α-melanocyte-stimulating hormone (α-MSH)

Reduces feeding via melanocortin receptors (MC4) in the arcuate nucleus and other hypothalamic regions.

ACE Inhibitors

Enzymes that cleave propeptides can be the target of drugs. Used to treat hypertension.

Angiotensin-converting enzyme (ACE)

Cleaves angiotensin I to a more active form, angiotensin II, a potent vasoconstrictor, and inactivates bradykinin, which is a vasodilator.

Alternative Splicing

Primary prepropeptide transcripts may be alternatively spliced to give multiple products with different actions. For example, calcitonin and CGRP are encoded by the same gene.

Calcitonin

Produced in the thyroid gland.

Calcitonin Gene Related Peptide (CGRP)

Made in some neurons; a potent vasodilator. CGRP receptor antagonists are useful in treating migraine.

Substance P

Involved in neurogenic inflammation and pain pathways in the dorsal horn of the spinal cord.

Large Dense Core Vesicles (LDCVs)

Found away from the active zone of the synaptic cleft; exocytosis requires large, transient increases in intracellular Ca2+.

G Protein-Coupled Receptors (GPCRs)

Nearly all neuropeptides bind to these receptors, many of which have multiple receptor subtypes.

Agouti-related peptide (AGRP)

Endogenous antagonist of the MC4 receptor, which increases feeding behavior.

Glucagon-like peptide-1 (GLP-1)

Has multiple peripheral actions and acts in the hypothalamus to reduce appetite & food intake.

Semaglutide

GLP-1 receptor agonist.

Orexin A and B (hypocretin 1 and 2)

Produced only in the lateral and posterior hypothalamus, but have very widespread projections. Stimulate feeding behavior and modulate reward/goal-directed behaviors.

Opioid Peptides

Include β-endorphin, enkephalins & dynorphins; formed from 3 different precursors but have some homologous features. Act on mu, kappa, and delta receptors.

Biased Agonists

Bind to mu opioid receptors & preferentially signal through Gαi, and recruit less arrestin-mediated signaling. Could be useful analgesic (pain reducing) drugs.

Purinergic Neurotransmitters

Derived from purine bases; include adenosine, adenosine triphosphate (ATP), and adenine dinucleotides (ApnA).

Adenosine Triphosphate (ATP)

Can be stored in vesicles and is released by increased intracellular Ca2+. Often colocalized with classic neurotransmitters.

Purinergic Receptors

Two families: P1 (activated by adenosine) and P2 (activated by ATP).

Adenosine Receptors (A1, A2A, A2B, A3)

P1 receptors; all 7-transmembrane/G protein-coupled receptors.

A1 Receptors

Gi receptors widely expressed in the CNS and have a very high affinity for adenosine. Activation is associated with anxiolytic, anticonvulsant, analgesic, and sedative effects.

A2A Receptors

Gs receptors concentrated in brain areas receiving high dopamine input; A2A adenosine receptor agonists oppose the effect of dopamine at D2 dopamine receptors in the dorsal striatum.

Methylxanthines

Act as antagonists at A1 and A2A receptors; include caffeine.

P2 Receptors

Activated by ATP; include P2X and P2Y receptors.

P2Y Receptors

GPCRs; their function is not well-understood.

P2X Receptors

Cation channels (Na+, Ca+, K+); activation causes rapid membrane depolarization. Involved in different forms of pain; targets for analgesic drug development.

Nitric Oxide (NO)

First confirmed gas neurotransmitter; derived from arginine and released by endothelial cells to cause vasodilation and from neurons.

Nitric Oxide Synthase (NOS)

Synthesizes NO from arginine. Three genes/enzymes exist: eNOS, nNOS, iNOS.

Endocannabinoids

Endogenous ligands for CB1 and CB2 receptors; include anandamide and 2-arachidonoylglycerol (2-AG).

CB1 Receptors

Widespread throughout the brain; primarily presynaptic and inhibit neurotransmitter release. Couple through Gi.

CB2 Receptors

Mostly found on peripheral immune cells with very limited CNS neuronal expression (mostly on microglia in brain). Couple through Gi.

Dronabinol

Synthetic THC; a CB1 receptor agonist that stimulates appetite and can be used to treat nausea and vomiting in chemotherapy patients.

Rimonabant

CB1 receptor antagonist; was used in Europe to treat obesity but was suspended due to reports of severe depression and suicidal thoughts.

Neurotrophic Factors

Proteins that affect the cell cycle, growth, differentiation, and survival of neurons (or glia).

Neurotrophins

A family of neurotrophic factors; include Brain Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4 (NT-4).

Tropomyosin Receptor Kinases (TrkA, TrkB, TrkC)

Receptor tyrosine kinases to which neurotrophins bind.

P75 Receptor

Binds with lower affinity to neurotrophins; can enhance Trk signaling or activate apoptosis.

Pain

The discomfort associated with tissue damage.

Nociceptors

The neural processes of encoding and processing noxious stimuli; transduce non-electrical signals to action potentials.

A delta (Aδ) fibers

Large myelinated axons that register pain quickly; respond to dangerously intense mechanical or mechanical + thermal stimuli.

C fibers

Thin, unmyelinated axons that conduct relatively slowly, producing lasting pain. Polymodal: respond to thermal, mechanical, and chemical stimuli.

Transient Receptor Potential (TRP) Channels

Heat-sensitive channels involved in transduction of nociceptive signals.

Hyperalgesia

Noxious stimuli are perceived as significantly more painful than if the injury had not occurred.

Allodynia

Stimulus that is normally not painful is now painful.

Neurogenic Inflammation

The painful, inflammatory response caused by the local release of pain-inducing and inflammatory mediators from neurons.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Reduce peripheral pain sensitization by blocking the production of prostaglandins. Inhibit cyclooxygenases (COX1 and COX2).

Periaqueductal Gray (PAG)

Opioids inhibit activity of inhibitory interneurons, increasing the activity of descending output neurons involved in pain modulation.

Locus Coeruleus (LC)

Noradrenergic; projects to the dorsal horn, exciting inhibitory interneurons, which release the opioid peptide enkephalin, which inhibits nociceptors and 2nd order neurons.

Raphe Magnus

Serotonergic; projects to the dorsal horn, exciting inhibitory interneurons, which release the opioid peptide enkephalin, which inhibits nociceptors and 2nd order neurons.

Opiate

Refers to alkaloids derived from the opium poppy. Includes morphine, codeine, heroin, and opium.

Opioid

Refers to any compound that acts on opioid receptors. Examples include endogenous NTs, opiates, semi-synthetics, and synthetics.

Naloxone (Narcan)

Used in opioid overdoses; causes death by respiratory depression.

Naltrexone

Used in opioid addiction.

Macrophages

In the periphery, mediate inflammation by releasing chemicals (eg interleukins) that attract other immune cells to the area and cause an inflammatory reaction.

Pattern Recognition Receptors (PRRs)

Expressed by macrophages; bind pathogen-associated molecular patterns (PAMPs) on the invading pathogen.

Lipopolysaccharide (LPS)

An example of a PAMP present on all Gram-negative bacteria.

Toll-Like Receptors (TLRs)

Examples of PRRs expressed by macrophages; TLR4 recognizes LPS.

Damage/Danger Associated Molecular Patterns (DAMPs)

Alarm signals associated with “self,” not a pathogen, but activate the same pattern recognition receptors on cells of the innate immune system; i.e., sterile inflammation.

Microglia

Resident macrophages in the CNS that also express PRRs.

(+)-Naltrexone

Blocks the effect of DAMPs and opioids at TLR4 receptors, preventing the inflammatory response of microglia.

Rewarding Stimulus

Intrinsically positive, or something to be approached. Stimulates pleasure, hedonic effects.

Reinforcing Stimulus

Increases the probability that behaviors paired with it will be repeated. Can be positive or negative.

Addiction

Behavioral pattern of drug abuse characterized by compulsive drug use, obsession in securing the drug, and a tendency to relapse after discontinuance.

Dependence

Physiological state of neuroadaptations produced by repeated drug administration, necessitating continued administration to prevent the occurrence of withdrawal symptoms.

Mesolimbic Dopamine Pathway

An important “reward pathway”; particularly ventral tegmental area to nucleus accumbens pathway.

TAAR1

Results in phosphorylation of reuptake transporters and consequent reversal of direction of neurotransmitter transport, so that DA/NE are pumped out of the axon terminal into the synaptic cleft.

Incentive-Sensitization

Model of addiction of how ‘wanting’ to take drug may grow over time, independently of ‘liking’ the drug.

Impulsivity

The inability to stop initiating actions.

Compulsivity

The inability to terminate ongoing actions.