CNS targets for pain treatment 14/4

Question 1

What is the gate control theory of pain?

Answer 1

“Why we rub a smack”

• tactile AB fibres syanpse onto inhibitory GABAergic interneurons, both of which then synpase onto the same projection neurons as c-fibres.
• Activation of AB fibres by tactile stimulation therefore results in GABAergic inhibition competeing with c-fibre input
• This can reduce nocioceptive pain transmission

Question 2

What are most common analgesics?

Answer 2

• Opioids e.g., morphine
• NSAIDS eg., ibuprofen
• Tricyclic anti-depressants e.g, amytriptyline
• Anticonvulsants e.g., lamotrigine

Question 3

What analgesics are currently in development?

Answer 3

• P2X4 antagonists
• NMDA GluN2B subunit antagonists
• chemokine receptor antagonists
• protease receptor antagonists

Question 4

What is the mechanism of action of opioids?

Answer 4

Opioid mu-receptor is thought to have the most anti-nociceptive actions.

Opioid receptors are found in many areas related to pain processing, from the spinal cord to PAG to higher pain processing centres

All opioid receptors are linked through G-proteins to inhibition of adenylate cyclase.

They also facilitate opening of K+ channels (causing hyperpolarization) and inhibit opening of Ca2+ channels (inhibiting neurotransmitter release).

In spinal cord, morphine inhibits release of substance P. There is a constant endogenous tone of descending inhibition - giving naloxone will therefore increase substance P during stimulation.

Question 5

Mechanism of NSAIDs

Answer 5

PGE2 phosphorylates glycine receptor (inhibitory), to antagonise it. This prevents Cl- entry into the cell. PGE2 therefore encourages hyperactivity of cells.
NSAIDs work by inhibiting cyclooxygenase, to reduce cyclooxygenase metabolising arachidonic acid into PGE2 (etc).

NSAIDs are known to work peripherally, but if they cross the BBB then this mechanism is also effective centrally.

Question 6

GABApentin mechanism of action

Answer 6

This is an anticonvulsant.

It has a similar structure to GABA, but it is not GABAergic.
Specific binding site is the α2δ subunit of voltage-dependent calcium channels.
Due to binding of VGCC, GBP inhibits glutamate release and interacts with the glycine site of NMDA receptor. This blocks pain signalling in the spinal cord.The exact mechanism of action is still uncertain

Question 7

NR2 Antagonists

Answer 7

NMDA receptor antagonists such as ketamine are effective in treating pain, however the widespread distribution of NMDA receptors means that they cause serious side effects. E.g., NMDA receptor activation in the hippocampus is required for LTP (memory)

GluNR2 subunits contain the binding site for glutamate. They have four different subtypes whose expression is spatially and temporally specific.

GluNR2B is largely found in the spinal cord.

GluNR2B antagonists are effective nocioceptors.

Question 8

How do microglia change in response to increased input from primary afferents?

Answer 8

They normally dormantly survey the parenchyma of the spinal cord.
After peripheral nerve injury, they become activtated

Morphological changes -> Become large, dense and retract protrusions

They increase expression of P2X4 and release BDNF and fraktalkine cleavage enzymes.

Question 9

Which two signalling pathways are activated by microglia during pain sensitization?

Answer 9

P2X4/BDNF

Fraktalkine pathway

Question 10

What is the P2X4/BDNF pathway implicated in pain senstitization?

Answer 10

Increased afferent stimulation causes P2X4 receptor activation. This becomes activated by ATP, causing BDNF release.

• BDNF activation of TrkB receptors in GABA-A expressing neurons results in down-regulation of potassium-chloride transporter and accumulation of chloride ions into the cell
• Therefore, GABA activation of GABA-A receptor results in chloride ions efflux and neuronal depolarization
• GABA therefore becomes excitatory, contributing to excitatory state of DH neurons in neuropathic pain.

Question 11

What could be two potential therapeutic targets within the P2X4/BDNF pathway for pain relief?

Answer 11

P2X4 antagonists

(Chloride channel) KCC2 enhancers - restore chloride ion gradients

Question 12

What is the fraktalkine signalling pathway implicated in pain?

Answer 12

Fraktalkine signalling may be a specialised form of communication between neurons and microglia.

Fraktalkine is a specialised chemokine which is embedded in the membrane of neurons.

Increased afferent input and the release of ATP results in activation of P2X7 receptors in microglia
• P2X7 receptor activation results in the release of the lysosomal protease cathepsin S
•Cathepsin S proteolitically cleaves the soluble chemokine domain of fractalkine from neuronal membranes
•Soluble fractalkine activates the CX3CR1 receptor in microglia activates the MAPK/p38 pathway and results in release of mediators such as cytokines that sensitise neurons

Question 13

What drugs could constiute a microglial strategy for neuropathic pain treatment?

Answer 13

P2X7 antagonists, Cathepsin S inhibitors, CX3CR1 antagonists and p38 MAPK inhibitors

Question 14

Which types of pain are NSAIDS effective in treating?

Answer 14

Inflammatory pain (it’s in the name). They are effective in treating inflammatory pain conditions stemming from autoimmune conditons such as rhuematoid arthritis.
They are less effective for degenerative conditions such as oesteoarthritis.

They are ineffective in treating neuropathic pain.

Animal models of inflammatory pain show good predictive validity of human responses to NSAIDS.

Question 15

What are the two broad strategies of analgesics?

Answer 15

1. Peripheral targeting. Finding mechanisms to block in the periphery means that the challenge of crossing the BBB does not need to be overcome
2. Central targeting. Targeting central mechanisms may be more effective in treating pain due to plasticity in the CNS that contributes to many chronic pain conditions.

Question 16

What is efficacy of different drug classes in treating neuropathic pain?

Answer 16

In general opioids are not useful for neuropathic pain.
NSAIDS are not useful for neuropathic pain.

Question 17

What types of pain is morphine (opioids) efficacious in treating?

Answer 17

Most types of chronic and acute pain, especially those associated with injury or inflammation.

It is highly effective in treating bone cancer pain, which can be modelled in rodents by intratibial injection of mammary tumor cells. This leads to significant weight bearing differences, which can be reduced by morphine.

Models of neuropathic pain such as sciatic nerve lesions are not so effecitvely treated with morphine.

Question 18

What is the efficacy of NSAIDs in treating bone cancer pain?

Answer 18

Bone cancer pain can be modelled in rodents by intratibial injection of mammary tumor cells.

COX-2 selective inhibitor NSAID at both 10 and 30 mg/kg significantly reduces hyperalgaesia and ipsilateral allodynia.

However, they are also disease modifying. 30mg/kg is effective in improving bone mineral density and radiological scores.

Question 19

Anticonvulsants as analgesics

Answer 19

Both epilepsy and neuropathic pain are associated with abnormal neuronal activity; therefore may be treated with anticonvulsants to either block excitatory mechanims or promote inhibitory mechanisms.

Examples:

Lamotrigine: sodium channel blocker

Carbamazepine: inhibits NA uptake and modulates voltage gated sodium channels. Thus, promotes descending inhibitory pathways and suppresses spontaneous neuronal activity.

Gabapentin: Binds to VGCa++ channels

Question 20

Antidepressants as analgesics

Answer 20

Their analgesic effect is indepedent of their mood altering effects - they increase the availability of monoamines the synapse. Their analgesic effect emerges within 1 week, whereas mood effects take a few weeks to emerge.

Tricylic antidepressants such as amitryptyline and nortryptyline. SNRIs such as duolexitine work. SSRIs are generally not effective.

They are the oldest and most effective treatment for neuropathic pain. Can be seen in mouse model of diabetic neuropathy (streptozotocin).

Question 21

Use of NK1R receptor antagonists as analgesics?

Answer 21

Expression of substance P by AB fibres is known to underly tactile allodynia, and substance P binding potentiates glutamate responses during central sensitisaiton.

However, NK1R antagonists are ineffective in clinical trials, depsite showing analgesia in animal models.

This is unlikely to be due to ‘species differences’ in the role of substance as it shows remarkable similarities in the distribution of both the peptide and NK1 receptors in the dorsal horn of the spinal cord. Furthermore, these mice have shown predictive validity for other analgesics,
It has been hypothesised that NK1R antagonism actually attenuates the response to stressful stimuli per say - as it reliably alters responses to maternal separation models, for example. This effect may therefore alter animal behavioural responses to stressful stimuli including pain - but this isn’t sufficient to induce analgesia in clinic.
The use of chimeric compounds that contain NK1R antagonist and an opioid agonist are currently being investigated, as there is a possibility that NK1R may reduce the dose of opioids needed for efficacy.

Question 22

What are the side effects of NSAIDs?

Answer 22

Their side effects severely limit their usage. These include gastrointestinal complications from milder dyspepsia to serious life‐threatening GI bleeding.
They also lead to nephropathy (damage and injury to the kidneys). Inhibition of cyclooxygenase reduced PGE2 (function of NSAIDs) but this causes reduced blood flow to the inner renal papillae of the kidneys, causing tissue death. In healthy individuals this does not occur normally (due to compensation) except when paracetamol and ibuprofen are combined.