Novel sensory targets for pain relief

Question 1

8 classes of current analgesics (Example and mechanism for each)

Answer 1

1. NSAIDs. Ibuprofen, asprin. Inhibit COX-1/2
2. Local anaesthetics. Lidocaine. Block voltage gated sodium channels.
3. Opioids. Morphine. Mu-opioid receptor agonists.
4. TRPV1 agonists. Capscasin. TRPV1 desensitisation.
5. Tricyclic antidepressants. Amitryptiline. Increasing monoamines and blocking sodium channel.
6. 5HT1 agonists. Agonist at 5HT1B and 1D receptors (and 1F)
7. Dissociative anaesthetics. Ketamine. Non-selective NMDA block.
8. Antiepileptics. Carbamazepine. Sodium channel block

Question 2

What are the risks and benefits for each class of analgesics?

Answer 2

1. NSAIDs. Mild/moderate pain & inflammatory pain. Ulcers, haemorrage.
2. Local anaesthetics. Local analgesia. Safe unless gets into circulation.
3. Opioids. Severe pain, inflammatory pain. Constipation, nausaea, withdrawal, tolerance, dependence.
4. TRPV1 agonists. Neuropathic pain. Cause pain initially.
5. Tricyclic antidepressants. Neuropathic pain CV changes, many side effects.
6. 5HT1 agonists. Migraine. Rash, blood conditions.
7. Dissociative anaesthetics. Neuropathic pain. Addictive, psychotic effects.
8. Antiepileptics. Migraine. CV changes.

Question 3

5 novel molecular targets for analgesics

Answer 3

1. nAChR agonists
2. Purinoreceptor antagonists
3. K+ channel agonists
4. ASIC channel antagonists
5. Cannabinoids

Question 4

nAChR agonists for analgesia

Answer 4

ACh signalling the CNS is associated with pain processing.

Naturally occuring nAChR agonists from frogs have strong analgesic activity. Synthetic compounds (ABT-594) mimicking the structure show analgesia in acute, peristant and neuropathic pain conditions.

This ABT-594 compound failed clinical trials due to a narrow therapeutic index (i.e., the side effect dose is close to the therapeutic dose). This is unsuprising due to the widespread role of nAChR activation.

Question 5

Purinoceptor antagonists for analgesia

Answer 5

ATP is released from cells when they become damaged, and is thus a signalling molecule that triggers inflammatory and nocioceptive responses.

P2X3 receptors are upregulated on sensory nerve fibres in mouse models of neuropathic pain. P2X3 antagonists showed efficacy in treating neuropathic pain in mouse models (but not inflammatory, acute or visceral). It failed clinical trials due to poor bioavailability. A second compound is currently in phase II trials.

P2X7 receptors are located on microglia and are implicated in inflammatory responses. Sustained activation results in cytolytic pore that unselectively lets substances flow in and out of the cell, leading to cell death. P2X7 KO mice and P2x7 antagonists show reduced inflammation in an arthritis model and reduced hyperalgesia and allodynia in a neuropathic pain model. P2X7 is currently in clinical trials.

Question 6

K+ channel agonists as analgesics

Answer 6

Kv7 channels are shown to be involved in phasic M currents, and their activity is required for setting excitability of the cell.
Agonists for Kv7 (Retigabine) hyperpolarise the cell and have been shown to be effective in persistant and neuropathic pain.
But Kv7 channels found in CNS and other peripheral nerve cells - non-selective and potentially dangerous. It was dropped for lack of efficacy.

Question 7

ASIC channel antagonists for analgesia

Answer 7

ASIC channels are proton sensing channels that are mainly sodium permeant

– Located on sensory neurones, taste cells and in the CNS

Pain inducing snake toxins (MitTx) activate ASICs

ASIC1a/3 toxin compounds from spiders and anenome are shown to be analgesic

Receptors found in: Skin • Muscle joints • GI tract • Heart (angina?)

There are currently no chemical compounds to antagonise ASIC