Pain & Analgesia

Question 1

The major inhibitory neurotransmitters in the dorsal horn of the spinal cord are:

Answer 1

• ⁻ Opioid peptides
• ⁻ Norepinephrine (NE)
• ⁻ Serotonin (5-HT)
• ⁻ Glycine
• ⁻ GABA
  
  • They all act pre-synaptically and post-synaptically to inhibit neurotransmission.

Question 2

1.Pre-synaptic inhibition:

Answer 2

mediated via reduced activity of voltage-gated calcium channels, which impedes presynaptic neurotransmitter release.

Question 3

2.Post-synaptic inhibition:

Answer 3

mediated primarily by enhanced chloride influx and potassium efflux (post-synaptic hyperpolarization), which reduces postsynaptic neuronal responses to excitatory neurotransmitters.

Question 4

Endogenous opioid peptides

Answer 4

• pro-opiomelanocortin -> β-endorphin
• pro-enkephalin -> enkephalins
• pro-dynorphin -> dynorphins

ii. Endogenous opioid peptides are receptor-selective:

• § Dynorphins act primarily on κ receptors
• § Enkephalins and β-endorphin act on μ and δ receptors.

Question 5

Norepinephrine (NE):

Answer 5

i. α2-adrenergic receptors (GPCR) agonist clonidine is sometimes used to treat pain, but adverse effects that include sedation and postural hypotension.
ii. Selective norepinephrine (NE) reuptake inhibitors have analgesic action.

Question 6

Serotonin (5-HT):

Answer 6

i. Mediated by 5-HT GPCRs
ii. 5-HT3 ligand-gated channel may be responsible for the excitatory actions of serotonin in the spinal cord.

Question 7

Cannabinoid receptors and the endogenous cannabinoids:

Answer 7

• anandamide and 2-arachidonylglycerol (2AG)
• CB1: expressed in the brain, spinal cord, and sensory neurons
• CB2: expressed in non-neural tissues, especially immune cells including microglia.
• CB1 or CB2 agonists or inhibitors of endocannabinoid metabolism, may prove useful for pain management.

Question 8

Peripheral Sensitization

Answer 8

• Allodynia; in which normally innocuous stimuli are perceived as painful
• Hyperalgesia; in which high-intensity stimuli are perceived as more painful and longer lasting than usual at the site of injury (zone of primary hyperalgesia).

Question 9

Central Sensitization

Answer 9

repetitive, high-intensity, synaptic transmission activates intracellular signal transduction cascades in dorsal horn neurons that enhance the response to subsequent stimuli.

Question 10

postsynaptic receptors are involved in the induction of

central sensitization

Answer 10

• AMPA, NMDA
• Metabotropic glutamate receptors
• Substance P (neurokinin) receptor: NK1
• BDNF (neurotrophin) receptor: TrkB.

Question 11

Neuropathic Pain

Answer 11

• loss of neurotrophic support
• the release of inflammatory cytokines from injured nerves and inflammatory cells Alters gene expression of nerve fibers
• increases peripheral and central sensitization of nociceptive fibers
• leads to the continued perception of injury that is characteristic of neuropathic pain.