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BMSc - Neuropharmacology and Behaviour > Mechanisms of Analgesia > Flashcards

Mechanisms of Analgesia Flashcards

1
Q

Describe the efferent, supraspinal ant nociception regulation of pain

A

Supraspinal anti-nociception is mediated by descending pathways from the brainstem:

  • Brain regions involved in pain perception and emotion (cortex, amygdala, thalamus and hypothalamus) project to specific brainstem nuclei
  • Neurons of brainstem nuclei give rise to efferent pathways that project to the spinal cord to modify afferent input
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2
Q

Describe important brainstem regions involved in efferent, modulation of pain (supraspinal anti-nocicpetion)

A 
PAG (midbrain) 
Locus coeruleus (pons) - NA to dorsal horn 
Nucleus Raphe Magnus (medulla) - 5-HT and enkephalinergic to dorsal horn
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3
Q

Describe the role of PAG in anti-nociception

A

Excitation via electrical stim of PG produced a profound analgesia

Endogenous opioids (enkephalins) or morphine and related compounds also cause excitation of the PAG (via inhibiting inhibitory GABA-ergic interneurons i.e. disinhibition)

Excitation of PAG results in excitation of NRM and LC which act to decrease nociception transmission in the DH of SC (descend via dorsolateral funiculus DLF)

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4
Q

What are the 3 mechanisms by which NA and 5-HT/enkephalin impacts in the DLF act as anti-nociceptive agents

A

Direct presynaptic inhibition
Direct post synaptic inhibition
Indirect inhibition

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5
Q

Describe the mechanisms of direct presynaptic inhibition in the anti-nociceptive effects of NA and 5HT/enkephalin in more detail

A

Inhibition of nT release from nociceptors (A-delta, c fibre) onto projection neuron
This works via GPCR (5HT metaboreceptors) to suppress the opening of voltage gated calcium channels and therefore calcium influx required for nT exocytosis and vesicle docking at the presynaptic membrane

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6
Q

Describe the mechanisms of direct post synaptic inhibition n the anti-nociceptive effects of NA and 5HT/enkephalin in more detail

A

Works via GPCRs opening K+ channels in the projection neuron causing hyperpolarization and reduced excitability

The effect of descending inhibition can be mimicked by exogenous opioids such as opioids. These work on GPRC to open voltage activated K+ channels. Threshold for action potential increased

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7
Q

Describe the mechanism of indirect inhibition n the anti-nociceptive effects of NA and 5HT/enkephalin in more detail

A

Works via activation of inhibitory interneurons (enkephalinergic and GABAergic) that suppress transmission by both pre and post synaptic mechanisms

Gating theory; myelinated Ab-beta non-nociceptor units act on inhibitory interneurons to increase activity

Increase of enkephalin (endogenous opioids)

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8
Q

Describe the action of opioids on the DLF

A

Inhibit K+ channels directly; hyperpolarizing the projection neuron

Mimic the activity of enkephalins on the inhibitory interneuron

Overall; suppression of excitability of projection neuron

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9
Q

How do analgesics reduced nociception?

A

Local action to decrease nociceptor sensitization in inflammation (NSAIDs)

Block nerve conduction (local anaesthetics)

Suppress the transmission of nociceptive signals in the DH of the SC (opioids and amitriptyline)

Activation (potentiation) of descending inhibitory controls (opioids)

Targeting ion channels upreg in nerve damage (carbamazepine)

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10
Q

What type of receptor is an opioid receptor?

A

Metabotropic via Gi/o

  • Inhibition of opening of voltage activated calcium channel of the central terminal of nociceptive neurons. Suppressed excitatory transmission release mediated by the Gi/o beta gamma subunit
  • Opening of K+ channels at the post synaptic membrane. Suppresses excitation of projection neurons. Mediated by Gi/o beta gamma subunit
  • Inhibition of adenylyl cyclase; mediated by the Gi/o alpha subunit. Decreased in abundance of cAMP in the cells.
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11
Q

What are the different forms of opioid receptors?

A

Mu; analgesic effects and major adverse SE

Delta; analgesia and proconvulsant

Kappa; analgesia at the spinal and peripheral level, activation assoc with sedation, dysphoria and hallucinations

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12
Q

Describe the respiratory side effects of opioids

A

Apnoea

Occurs via blunting of the medullary resp centre to carbon dioxide (hypercapnic response; pain opposes this)

Involves mu and delta

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13
Q

Describe the cardiovascular side effects of opioids

A

Orthostatic hypotension

Reduced symp tone, and bradycardia (via actions on the medulla)

Histamine evoked vasodilation - morphine can cause mast cell degranulation which can trigger bronchospasm in asthmatics

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14
Q

Describe the GI side effects of opioids

A

N+V
Constipation
Increased intrabiliary pressure

Action on CTZ (out with BBB)

Incr smooth muscle tone, decreased motility via enteric neurons

Involves mu and delta

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15
Q

Describe the CNS SE of opioids

A

Confusion, euphoria, hallucinations, dizziness, myoclonus, hyperalgesia

Occurs to different degrees dependent on the specific opioid drug and receptor subtypes activated

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16
Q

Describe morphine

A

Widely used for severe pain

Hydroxyl group at 3 and 6 Carbon
Metabolised in the liver by glucuronidation at the 3 and 6 positions yielding M3G that is inactive and M6G that retains analgesic activity and is excreted by the kidney (water soluble)

Can be given IV, IM, s/c or PO

Chronic oral administration; oramorph or MST (12-14 hrs)

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17
Q

Describe diamorphine (3,6-diacetyle morphine, heroin)

A

Acetyl groups (lipophilic) at 3 and 6. MORE lipophilic than morphine. Enters CNS much better than morphine due to diffusibility of BBB

Severe post-op pain

18
Q

Describe coedine

A

3-methoxy substituent at 3 carbon group with a methyl group

Naturally occurring weak opioid

Pro-drug; requires metabolism to become active. This occurs via hepatic metabolism

Codeine molecule is demethylated to morphine via CYP2D6 and CYP3A4 (subject to polymorphisms)

Additional anti-diarrhoeal and antitussive activity

Semi-synthetic derivatives with a higher potency include oxycodone and hydrocodone

19
Q

Describe fentanyl

A

75-100x more potent that morphine

Part of phenylpiperidine class of opioid agonist

Given IV to provide analgesia in maintenance anaesthesia (remifentanil - rapid onset and offset) to reduce GA required

Transdermal and buccal delivery in chronic pain states

20
Q

Describe pethidine

A

Used in acute pain, esp labour

Rapid onset and offset of action when given IV, IM or s/c

Should not be used in conjunction with MAO inhibitors (causes excitement, convulsions and hyperthermia)

Norpethidine is a neurotoxic metabolite (seizures)

21
Q

Describe buprenorphine

A

Partial agonist

Useful in chronic pain with patient controlled injection systems

Slow onset but long duration of action

IV or sublingually

22
Q

Describe tramadol

A

Weak mu opioid receptor agonist

Exerts significant analgesic action by potentiation of descending supraspinal serotonergic (NRM) and adrenergic (LC) systems

Given PO

AVOID in patients with epilepsy

23
Q

Describe methadone

A

Weak mu agonist of phenyheptylamine class with additional actions at other sites in CNS such as K+ channels, NMDA glu receptors and 5-HT receptors

Given PO, with a long duration of action (1/2 >24hrs)

Useful in tx of chronic pain, and terminal cancer

Assists in withdrawal from “strong opioids” such as heroin

24
Q

Describe the relationship between half life and addictive potential

A

Agents with abuse potential that have a short half life are more addictive than those with a long half life

25
Q

Describe naloxone

A

Competitive antagonist at mu receptors (lesser extent to kappa and delta)

Used to reverse opioid toxicity (i.e. resp and/or neurological depression)

Give incrementally with IV, however can be given IM and s/c

SHORT 1/2. Clinically, you must monitor the effect of naloxone very carefully, titrating the individual dose, and frequently to that required reverse opioid toxicity

The opioid will have a longer half life than naloxone.

26
Q

Describe naltrexone

A

Similar to naloxone, but orally available and with a much longer half life

27
Q

Describe alvimopan and methylnaltrexone

A

Do NOT enter CNS

Reduce GI effects of surgical and chronic opioid agonist use

28
Q

Describe NSAIDs

A

Widely used to reduce mild/mod inflammatory pain

Analgesic, antipyretic and anti-inflammatory actions

Inhibit the synthesis and accumulation of prostaglandins byCOX1 and Cox 2

29
Q

Describe the pathway from phospholipids to prostaglandins

A

Phospholipids = arachidonic acid via phospholipase A2

Arachidonic acid to endoperoxides via COX 1 + 2

Endoperoxides to prostaglandins (PGE2, PGD2)

30
Q

What are the effects of prostaglandins?

A

Hyperalgesia
Allodynia
Pain

31
Q

Where do NSAIDs (aspiring, ibuprofen, naproxen, diclofenac, indomethacin) act to prevent prostaglandin production?

A

COX-1 and COX-2

Therefore, prevents the formation of endoperoxides via arachidonic acid

32
Q

Where do COX-2 selective inhibitors (etoricoxib, celecoxib, parecoxib) act?

A

COX-2 to prevent creation of endoperoxides from arachidonic acid

33
Q

Describe the difference between COX1 and COX2

A

COX1 is constitutively active
COX2 is induced locally at sites of inflammation by various cytokines

Therapeutic benefit is largely derived from inhibition of COx2

34
Q

Do NSAIDs act peripherally and centrally?

A

Yes

Suppresses the decrease in the activation threshold of the peripheral terminals of nociceptors that is caused by PGEs

Decrease recruitment of leucocytes that produce inflammatory mediators

If cross BBB, suppress the production of pain-producing prostaglandins in the DH of the spinal cord (for example, reduce the action of the inhibitory nT glycine)

35
Q

Where does paracetamol act?

A

No anti-inflammatory activity

Acts only centrally

Precise mechanism is still debated but may involve several of its metabolites

36
Q

Why is long term use of NSAIDs not reccomended?

A

GI damage; PGE2 produced by COx1 protects against the acid/pepsin environment

Nephrotoxicity can occur due to inhibition of COX2 constitutively expressed in the kidney. Inhibition can compromise renal haemodynamics

37
Q

Describe conditions whereby neuropathic pain predominates

A 
Traumatic nerve, spinal cord, or brain damage (e.g. stroke)
Trigeminal neuralgia 
Diabetic neuropathy 
HIV/AIDs neuropathy 
Post-herpetic neuralgia 
MS 
Phantom limb pain
38
Q

Does neuropathic pain respond to typical analgesics?

A

No; no response to NSAIDS and relative insensitivity of opioids

There is evidence that there is downregulation of mu opioid receptors, or reduced signalling via such receptors occurs following nerve injury

39
Q

Which drugs are used to treat neuropathic pain?

A

Gabapentin and pregabalin

TCAs

40
Q

Describe the gabapentinoids

A

Reduced cell surface expression of alpha-2 delta-1 subunit of voltage calcium channels (high voltage activated sub-group) which are upregulated in damaged sensory neurons. Alpha-2 delta-1 isoform is associated specifically with excitatory neurons

Decrease in abnormally enhanced release of nT, such as glutamate and sub P, from the central terminals of nociceptive neurons

Gabapentin; migraine prophylaxis

Pregabalin; painful diabetic neuropathy

41
Q

Describe TCAs for neuropathic pain

A

Act centrally by decreasing the reuptake of NA (and 5-HT)

Duloxetine and venlafaxine additionally decrease the reuptake of 5-HT

SSRIs do NOT provide analgesia`; suggesting the important role for NA

42
Q

Describe carbamazepine in neuropathic pain

A

Blocks subtypes of voltage activated sodium channels which are upreg in damaged nerve cells

1st line to control pain intensity and frequency of attacks in trigeminal neuralgia

BMSc - Neuropharmacology and Behaviour (27 decks)

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