Opioids Analgesics Flashcards

Question

Describe VA Ca2+ channels Cav 1.1-1.4

Answer 1

CaV 1.1-1.4; all sensitive to dihydropyridine (specific antagonist) = L type calcium channel (channel supports currents that are long lasting and therefore show less inactivation) Excitation-contraction coupling of cardiac myocytes Hormone release; regulates transcription, synaptic regulation, nT release from sensory cells

Answer 2

No specific antagonist T type channel; transient, inactivate more rapidly then L type Pacemaker cells; repetitive firing

Answer 3

R type; resistant to inactivation Selective antagonist; SNX-482 Dendritic calcium transients

Answer 4

N current; nerve terminal Found on nerve cell terminals and dendrites Controls nT release; dendritic Ca2+ transients; hormone release

Answer 5

P/Q current; purkinje cells of cerebellum with a specific splice variant nT release, dendritic calcium transients, hormonal release

Answer 6

CaV 2.1 and 2.2 Located at nerve terminals where they can affect nT release These can be inhibited by opioid binding

Answer 7

L-type; cell soma, Influences gene expression T-type; participate in rising phase of action potential as it travels through axon hillock N and P/Q type; presynaptic where they control calcium entry into synaptic terminal; instrumental on vesicle docking and nT release

Answer 8

Beta gamma subunit of G protein binds to calcium channel to exert its effects - inactivation Presence of DAMGO there is an inhibition of part of the voltage activated calcium current (but not completely) - therefore suggests that there are other types of calcium channel types in the cell (not just N, P/Q) such as resistant L or T type calcium channels

Answer 9

Adaptation that occurs in the neurons that respond to neurons leading to reduced sensitivity and reduced analgesia However, this is not a reduction in efficacy but instead a reduction in potency - higher doses are required to create the same level of analgesia

Answer 10

Opioid induced hyperalgesia Pain initially goes down on exposure to morphine, after prolonged exposure there is a paradoxical recovery of pain perception, but individuals can become hyperalgesic This is due to tolerance to endogenous opioid production - lack of potency of exogenous analgesics but also a decline of innate ability to resist pain via endogenous opioid signalling mechanisms Stimuli that previously doesn't cause pain becomes painful (allodynia) resulting in a hypersensitivity to pain (hyperalgesia)

Answer 11

``` Reward = addiction Resp depression Immunosuppression Constipation Hyperalgesia Tolerance/ dependence ```

Answer 12

Receptor tolerance: decreased surface receptor, decreased receptor coupling, decreased receptor protein, decreased receptor RNA Cell tolerance and withdrawal: initially decreased cAMP, with then an adaptation. Therefore on removal of the opioid, there is an unmasked hypertrophy of cAMP System tolerance and withdrawal: feedback circuits adapt Synaptic plasticity in tolerance and withdrawal: well established at GABAergic synapses. increased AMPAR insertion; increased LTP to drug seeking behaviour

Answer 13

Selective Nav and Kv ligands Cav, TRP and P2X antagonists Biased GPCR signalling GPRC dimers

Answer 14

``` Opioid receptors Cannabinoid receptors mGluRs GABA AMPA/ NMDA Microglial cells Astrocytes ```

Answer 15

Yes; tail withdrawal assay | 10mg/kg a day; shows tolerance by day 4

Answer 16

Yes; MOR +/- mice causes a rightward shift in the dose response to morphine MOR -/- mice show no analgesic affects in response to morphine analgesia

Answer 17

``` Analgesia Reward Resp depression Immunosuppression Constipation Tolerance, withdrawal and dependence ```

Answer 18

The effect of morphine tolerance was abolished with no disruption of analgesia Peripheral mu opioid receptor expression on nociceptors is required for full analgesic tolerance Interesting research to lead to development of novel analgesics which antagonist the peripherally located mu opioid receptors - hypothetically, this would decrease tolerance with no effects on central analgesic effects

Answer 19

Primarily due to beta arrestin protein 2 (bind to GPCRs)

Answer 20

B-Arr2 will endocytose mu receptors via formation of clathrin coated pits. This allows for recycling of the receptor to be reinserted to the membrane without the agonist present. Additionally brings kinases such as MAPK, Src, Akt to the receptor to phosphorylate downstream effectors Can result in lysosomal degradation of the mu receptor

Answer 21

``` Lack of tolerance development Decreased resp depression Decreased constipation Increased reward Increased basal analgesia mediated by constituently active MOPrs ```

Answer 22

Shift in dose response to analgesia; show a basal level of tolerance Apply morphine daily; much more profound tolerance to WT No. of Mu opioid receptors is critical to the rate of analgesic tolerance develops

Answer 23

Delta doesn't play much of a role in morphine analgesia (-/- DOP show similar dose dependency to morphine at WT) Morphine tolerance is greatly diminished in -/- and +/- mice DOP participates in tolerance

Answer 24

Formation of heterodimers Mu and delta receptors can combine and influence each others properties This heterodimer has distinctive properties This can occur in the SC and DH neurons

Answer 25

DOPr recruits B-arr2 to MOPrs These heterodimers recruit b-arr2 in the absence of an agonist TOLERANCE

Answer 26

Delta -/- and +/- show resistance to the development of tolerance Antagonism of DOPs reduced morphine tolerance Bivalent drugs with MOP and DOP antagonist may be advantageous The bivalent opioid MDAN-21 analgesic causes little tolerance and dependence in mice

Answer 27

No; after 30 mins of exposure, morphine fails to cause endocytosis of mu opioid receptor This analgesia shows tolerance Mu opioid receptors become phosphorylated, with increased expression of B-arr2 = densitization

Answer 28

Yes; rapid endocytosis of mu opioid receptors This analgesic mechanism does not cause tolerance Therefore this result is the complete opposite of what is expected (you would associate tolerance with an internalization of mu opioid receptors)

Answer 29

Receptor Activation Versus Endocytosis -- endocytosis resensitized receptors Agonists that activate receptors without inducing endocytosis cause more tolerance because endocytosis allows for re-sensitization of desensitized receptors This was proposed to explain greater tolerance induced by on-internalizing agonist morphine

Answer 30

Agonist mediated phosphorylation after its bound the agonist In order to recruit b-arr the mu receptor must be phosphorylated at the C-terminal. This phosphorylation occurs at theoronine and seronine residues

Answer 31

Biased agonists bind to opioid receptors If balanced; agonists activate a range of different types of kinases to lead to G protein signalling and B-arr2 recruitment However; the agonists can be biased G-protein biased ligand (endogenous opiate peptides) leads to activation of GRK2/3 --> recruitment of B-arr2 which allows for internalization of receptor (no tolerance) B-arr biased ligand (alkaloids e.g. morphine) leads to activation of GRK5/6 --> activation of B-arr2 in a conformation that results in downstream signalling and NO internalization of mu (TOLERANCE)

Answer 32

DAMOG; highest levels of G1 activation. Highest levels of B-arr2 recruitment Morphine; Intermediate levels of G1 activation, much lower B-rr2 recruitment PZM21; similar G activation to morphine, no b-arr2 recruitment

Answer 33

Functionally selective mu opioids receptor which produced mu opioid receptor mediated G1 signalling with a similar potency and efficacy as morphine, but much less/no B-arr2 recruitment Biased novel mu receptor agonist

Answer 34

Hotplate analgesia; effective response. Measures the licking of paw after exposure to a hot plate (increased analgesia, reduced licking) Tail flick is a reflexive response

Answer 35

Hotplate analgesia - very similar to morphine Tail-flick analgesia - very limited effect Can therefore postulate that PZM-21 has its effects out-with the CNS and modulates the behaviour towards pain

Answer 36

PZM-21 causes less constipation than morphine PZM-21 causes much less resp depression (resp frequency) than morphine This is relevant to the danger of opioids However, further studies have demonstrated that it may act more like a partial agonist and puts into question the decreased resp depression assoc with PZM-21

Answer 37

Low intrinsic efficacy for Gi can explain an improved side effect profile Likely partial agonists Increased therapeutic window as the intrinsic efficacy goes down (inverse correlation) Improved therapeutic drugs are less to do with bias but more to do with G protein efficacy

Answer 38

G protein signal leads to phosphorylation of opioids receptor B-arr2 recruitment and arrestin binding leading to endocytosis

Answer 39

Decreased cAMP Decreased calcium Increased potassium Increased MAPK, Scr and Akt

Answer 40

Regulation of the constitutive activity and recycling of mu opioid receptors in the DRG

Answer 41

Prevents morphine tolerance in inflammatory hyperalgesia Tail withdrawal latency; again prevents morphine tolerance quite significantly

Answer 42

No; no change in morphine or basal tail withdrawal latencies **Inhibition of Src Kinase can prevent morphine tolerance

Answer 43

Yes; morphine alone for 3 days, after 3 days with dasatinib, there was reversal of morphine tolerance

Answer 44

Neuropathic and inflammatory pain Phosphorylates NMRAR to enhance the response == hyperalgesia Hub for NMDA receptor regulation We know NMDA receptors are involved in pain due to the action of ketamine NMDA receptors are responsible for the aspects of morphine evoked tolerance

Answer 45

Naloxone and methylnaltrexone (mu opioid antagonist) Dasatinib (Scr) Ketamine (NMDA) Rapamycin (mTORC1)

Answer 46

Could complicate and hinder recovery Impact on the need for prolonged opioid analgesia

Answer 47

Simple analgesia; paracetamol, NSAIDs Anti-neuropathic drugs and atypical analgesia; gabapentinoids, ketamine, magnesium, alpha 2 adrenergic agonists, steroids, IV lidocaine Invasive techniques; nerve blocks with LA

Answer 48

Endogenous opioids contribute to insensitivity to pain in humans and mice lacking Na+ channel NaV1.7 Upregulation of endogenous opioid release from nociceptive peptides

Answer 49

Endogenous opioidogenic dysregulation Reduction in regions in which opioid systems are found Reduction in PET imaging analysis of mu opioid receptor expression In some situations in which pain is enhanced; there is evidence for a dysfunctional endogenous opioid system

Answer 50

Yes; can stimulate endogenous opioid systems

Answer 51

Placebo effects are mediated by endogenous opioid activity on mu opioid receptors

Answer 52

Inflammatory pain decreases even when the inflammation is still present This is due to an upregulation of endogenous opioids When naltrexone is administered, the inflammatory hyperalgesia returns. This suggests that there is endogenous opioid activity Tissue injury produces muR constitutive activity that represses spinal nociceptive signalling for months

Answer 53

Dam number of sorties Much more in restricted bedding paradigm

Answer 54

CFA to evoke inflammatory sensitivity ELA mice show statistically significant enhancement of mechanical withdrawal threshold. Prior to application of the adjuvant, there is an upregulation of the analgesic response in mice When exposed to adjuvant; both control and ELA mice show heightened mechanical sensitivity ELA mice tend to be more resistant to acute pain. However, ELA mice show increased tolerance to upregulated mu constitutive opioid receptor function. Greater degree of chronic pain in ELA mice

Answer 55

Enhanced resilience to noxious heat in the acute setting (basal tail latency) However, the tail withdrawal latency declines, similar to inflammatory hyperalgesia paradigm Increased tolerance in ELA

Answer 56

Dose response relationship to morphine is shifted to the right for ELA mice. Consistent with increased tolerance; shift of the dose response relation ship to the right Tolerance develops rapidly and to a much greater extent Upregulation of endogenous opioid signalling which then primes the receptors to tolerance when exposed to exogenous alkaloid molecules such as morphine

Answer 57

Study of heritable phenotype changes that do not involve alteration in the DNA sequence External modifications to DNA that turns genes on or off with no modifications of DNA sequence, but instead how these cells read genes. Epigenetics alter the physical structure of DNA; not the molecular sequence

Answer 58

ELA gives rise to altered neural signals which influence regulatory genes within the cell - influences acetylation and regulation of pain, and opioid receptors Epigenetic markers control where and how much protein is made by a gene, effectively turning it on or off, thereby shaping how brains and bodies develop

Answer 59

Thalamus; reduction in mu opioid receptor expression (esp female mice - pain sensitivity between males and females varies)

Answer 60

Upregulation of delta expression in the spinal cord; stat significantly in male and female mice This upregulation of DOR in the spinal cord gives rise to increased mu-delta heterodimers which show a greater tendency to tolerance development (ability to pre-recruit b-arr2) Altered pain signalling = enhanced tolerance

Answer 61

Yes; children and adolescents with ACEs had an increased risk for chronic pain, and this association increased in a dose-dependent fashion (strongest associations included financial instability, living with a mentally ill adult or having experienced race discrimination)