Analgesics and Opiods Flashcards
Stimulation of periaqueductal grey and nociception
stimulates analgesia in which animal can respond to touch, pressure, and temperature still
Neurons in PAG path
- Excitatory connections neurons of rostroventral medulla
2. Seratonergic neuron axons project though D region spinal cord where form inhibitory connections w/ SC neurons
noradernergic system originating locus coerulues and other nuclei of the medulla and pons and analgesia
- this noradernergic descending system has projections that inhibit neurons in DH through direct and indirect synaptic actions -> suppression nociceptive neurons in DH
- this endogenous pain suppression pathway triggered by emotions or expectation (brain) can override nociceptive input
How do drugs reduce pain
analgesics can inhibit nociceptive:
- transduction
- transmission
- projection
- perception
- promote intrinsic analgesia
reduce pain inhibiting transduction
- directly or indierectly (via GPCRs) inhibit nociceptive sensors (TRP/ P2X) diminishing generator potentials
- promote K+ channel activity hyper polarizing nociceptor -> harder to get action potential
reduce pain inhibit transmission
- inhibit Na+ channels b/c voltage-gated Na+ channels transmit pain
pain projection through CNS how
- nociceptive signals propagated in CNS via glutamatergic synapses
- voltage gated Ca2+ channels -> glutamate released
reduce pain projection and propigation through CNS
- antagonize NMDA receptors
- promote K+ channel activity
reduce pain promoting intrinsic analgesic pathways
- block seratonin/ noradrenerin reuptake
- these drugs affect other brain activities
Molecular mechanism and neural circuit opiate action
- morphine and other opiates interact w/ specific receptors on neurons in SC and brain
- isolation endogenous neuropeptides w/ opiate-like activities at these receptors
opiates
- naturally occurring alkaloids found in opium poppy plant
- morphine
opioids
- any substance that binds body’s opiod receptor sites
- natural and synthetic alkaloids and endogenous peptides
opioids vs opiates
all opiates are opioids BUT not all opioids are opiates
morphine opioid or opiate?
both
Opioid receptor classes and what type receptor are they
- u (mu MOP)
- s (delta: DOP)
- k (kappa: KOP)
- orphanin FQ (N/OFQ)
- these are all GPCRs
Opioid Mechanism of action
- activate opioid receptor ->
- inhibition voltage-sensitive Ca2+ channels in presynaptic neuron -> less NT released
- activation inwardly rectifying K+ channels (GIRKs) in post synaptic neuron -> membrane hyperpolarization
- modulation cAMP-gated K+ channels
These activities -> attenuation neuronal excitability and reduction in neurotransmitter release
endogenous opioid peptides
- processed from large polypeptide precursors by enzymatic cleaveage
- distributed widely in CNS; individual peptides at sites processing or modulation nociceptive information
side effects opiods
- constipation
- sedation
- dizziness
- nausea
- V+
- physical dependence
- tolerance
- respiratory depression
- confine administration to SC or periphery to minimize side effects
capsaicin
- approved for topical treatment neuropathic pain
Additional info learn if time
- selectively activates TRPV1 channel -> indirect inhibition mechxnosensitive Piezo channel -> analgesia
NMDA receptor antagonist
- inhibits post-synaptically localized NDMA receptors which play central role in pain sensitization -> analgesia
- some of these drugs enhance effects NDAIDs, Gabapentin, and opiods
Cannabinoids
- endogenous analgesics
- activate CB1 GPCRs (couple with Gi) -> suppress voltage-gated Ca2+ channels and promote K+ channels (making membrane harder to depolarize)
- opioid overdose can ->
respiratory depression, V+ constipation
reversal agents opiods
- naloxone antagonizes u opioid receptors
- altipamezole reversal agent demedetomidine (kicks off agonists from alpha-2 adrenergic receptor)
- flumazenil reverses benzodiazepines (kicks off agonists from GABAA receptor)
reasons for failures of targeted analgesic research
- complex neurobio
- inadequate animal models
- difficulty reaching optimal therapeutic dose
- inability cross blood brain barrier
- lack specificity and off target effects
- high placebo response rate
- lack of reliable biomarker
progress in new generation of analgesics
- developing novel small molecules to target important plays in pain pathway
- developing structure-based drug designs with hopes biased opiods that inhibit G-protein pathways (pain) but not B-arrestin cascade (respiratory depression and addiction)
G-Protein Coupled receptor summary
- 7 transmembrane helical proteins
- alphasubunit is GDP bound in resting state when activated by ligand binding to receptor -> conformational change or alpha subunit-> alpha subunit release GDP-> GTP binds alpha subunit -> conformation change -> alpha subunit dissociates from receptor and beta and gamma subunits -> free GTP bound alpha subunit which can effect other proteins in cell
GAs can activate
-AC -> cAMP -> PKA (pathway activated) (PKA= protein kinase A)
GAi subcalss
- inhibit cAMP and in turn inhibit pKA
Gq
- PIP2-> DAG and IP3 -> PKC (protein kinase C)
