Snake Venom Types, Neurotoxins, and Opioid Pharmacology

Vipers

Long hollow hinged fangs that fold against roof of mouth when not in use; example rattlesnakes

Elapids

Fixed fangs; cobras are classic elapids and are often strongly neurotoxic

Colubrids

Rear-fanged snakes with grooved rather than hollow fangs; most are nonvenomous

Neurotoxins

Venoms that target the nervous system especially neuromuscular transmission

Neurotoxin mechanisms

Block nAChRs inhibit neurotransmitter release or cause uncontrolled neurotransmitter release

Three-finger toxins (3FTx)

Major neurotoxin family found especially in elapid venoms

Dendrotoxins

Neurotoxins that block potassium channels

Hemotoxins/Cytotoxins

Venoms that affect blood vessels clotting and tissue integrity

Hemotoxin mechanisms

Disrupt clotting cause tissue necrosis and destroy extracellular matrix proteins

SVMPs

Snake venom metalloproteinases involved in hemorrhage and tissue destruction

Myotoxins

Venoms that directly damage skeletal muscle causing necrosis

Effects of myotoxins

Release myoglobin potassium and intracellular contents from muscle cells

Polyvalent antivenom

Antivenom effective against multiple snake species

α-Latrotoxin (α-LTX)

Black widow toxin that forms pores in neurons causing massive calcium influx

Normal neurotransmitter release

Controlled by localized Ca²⁺ influx SNARE proteins and synaptotagmin

α-LTX initial mechanism

Binds neurexin and latrophilin tetramerizes inserts pore and causes massive neurotransmitter release

α-LTX sustained effect

Vesicle depletion leading to weakness and paralysis after hyperexcitation

Arizona bark scorpion venom

Targets voltage-gated sodium channels in autonomic neurons without destroying neurons

Box jellyfish venom

Causes leakage of ions proteins and cell components leading to cell death

Conotoxins

Cone snail toxins that target ion channels and neurotransmission

Evolution

Change in a population over time through inherited genetic variation

Mutations

Random DNA changes not caused by organism need

Evolution does not occur in individuals

Populations evolve not single organisms

α-neurotoxins

Cobra venom toxins that bind nicotinic acetylcholine receptors at NMJs

nAChR resistance

Amino acid substitutions in receptor α1 subunit can reduce toxin binding

Opiates

Natural alkaloids directly from opium poppy such as morphine and codeine

Opioids

All drugs that act on opioid receptors including natural semi-synthetic and synthetic drugs

Semi-synthetic opioids

Modified natural opiates such as heroin hydrocodone and oxycodone

Synthetic opioids

Fully synthetic drugs such as fentanyl methadone and tramadol

Ebers Papyrus

Ancient Egyptian medical text describing opium use for pain and crying children

Main opioid receptor families

MOR DOR KOR and NOP

MOR endogenous ligand

β-endorphin

DOR endogenous ligand

Enkephalins

KOR endogenous ligand

Dynorphins

NOP endogenous ligand

Nociceptin/orphanin FQ

Why humans have opioid receptors

To regulate pain stress reward motivation and gut activity

Opioid receptors

GPCRs that inhibit neuronal signaling and are not ion channels

Gi GPCR opioid effect

Decrease sodium influx decrease calcium entry and increase potassium efflux

Result of opioid receptor activation

Reduced neurotransmitter release and decreased neuronal firing

Nociceptors

Specialized sensory neurons that detect tissue damage

TRPV1

Common nociceptor ion channel activated by heat acidity and inflammation

Why opioids are effective

They can block severe otherwise unmanageable pain

Why opioids feel good

MOR activation increases dopamine release in nucleus accumbens reward pathway

How MOR increases dopamine

Inhibits GABA interneurons which disinhibits dopamine neurons

Major opioid problem

High addiction and overdose risk

Tolerance

Reduced drug effect after repeated exposure requiring higher doses

Mechanisms of opioid tolerance

MOR desensitization phosphorylation β-arrestin recruitment and internalization

Opioid-induced hyperalgesia (OIH)

Increased pain sensitivity after chronic opioid use

A118G mutation

MOR mutation associated with reduced signaling and higher opioid seeking

Respiratory depression

Opioids suppress brainstem respiratory circuits causing slowed or stopped breathing

pre-Bötzinger complex

Brainstem respiratory rhythm center heavily involved in opioid overdose death

Why relapse is dangerous

Tolerance falls during abstinence so old doses can become fatal

Naloxone

MOR antagonist that blocks opioid binding and reverses overdose

Heroin

Semi-synthetic opioid first synthesized from morphine in 1898

Why heroin is unique

More lipophilic than morphine so it crosses BBB rapidly

Blood-brain barrier (BBB)

Specialized barrier limiting entry of large or hydrophilic molecules into brain

6-MAM

Heroin metabolite that rapidly enters brain and converts to morphine

Fentanyl

Extremely potent synthetic opioid requiring very small doses

Why fentanyl is dangerous

Small amounts are lethal and easily mixed into counterfeit pills

Bioavailability

Fraction of active drug reaching systemic circulation

First-pass effect

Liver metabolism that reduces oral drug availability before circulation

Phase I metabolism

Liver reactions that chemically modify toxins and drugs

Phase II metabolism

Liver reactions adding hydrophilic groups for excretion

Morphine oral bioavailability

Only about 30 percent reaches circulation due to first-pass metabolism

Codeine

Prodrug activated by CYP2D6 into morphine

Prodrug

Drug requiring metabolic activation to become active

Half-life

Time a drug remains active in body

Potency

Amount of drug needed to produce effect

Efficacy

Maximum effect drug can produce

Sufentanil

Medical opioid about 5 to 10 times more potent than fentanyl

Carfentanil

Extremely potent animal tranquilizer about 100 times stronger than fentanyl

Why poppy seeds can trigger opioid tests

Trace morphine and codeine contamination from poppy latex

Fractionation

Separating crude mixtures based on chemical properties

Why poisonous elements are poor medicines

Low specificity broad tissue damage and narrow therapeutic windows

Bradykinin-potentiating peptides (BPPs)

Venom peptides that inhibit ACE and lower blood pressure

ACE

Enzyme involved in blood pressure regulation targeted by BPPs

Ziconotide

Cone snail-derived pain drug targeting N-type calcium channels in dorsal horn

Nicotinic acetylcholine receptor (nAChR)

Receptor essential for neuromuscular transmission and muscle contraction

Organophosphorus nerve agents

Compounds that inhibit acetylcholinesterase (AChE)

Dual-use research

Legitimate research that could also be misused for harm

Field color tests

Fast presumptive forensic tests with risk of false positives and negatives

ICP-MS

Technique best for detecting metals like lead arsenic mercury and thallium

GC-MS

Technique best for volatile small molecules like drugs solvents and alcohols

LC-MS/LC-MS-MS

Technique best for larger polar fragile or nonvolatile molecules

Mass spectrometry

Identification method using molecular mass and fragmentation patterns

Immunoassays

Antibody-based tests such as ELISA used for rapid targeted toxin or drug screening