Mechanisms of neuropathic pain

Question 1

Question: What is neuropathic pain and how is it classified?

Answer 1

Answer: Neuropathic pain is caused by damage to or disease affecting the somatosensory nervous system. It can be classified into:

Peripheral neuropathic pain: Caused by traumatic, metabolic, or infectious events (e.g., post-amputation, trigeminal neuralgia, radiculopathy, polyneuropathy).

Central neuropathic pain: Results from conditions such as post-stroke, spinal cord injury, and multiple sclerosis.

Question 2

Question: What are some commonly used drugs for neuropathic pain, and why do they show low efficacy?

Answer 2

Answer: Common drugs include:

TCA (tricyclic antidepressants)

Gabapentinoids (e.g., Gabapentin)

SNRIs (serotonin-noradrenaline reuptake inhibitors)

Opioids, Lidocaine, Capsaicin.
These drugs show low efficacy because neuropathic pain mechanisms are complex and involve both peripheral and central pathways. No single drug addresses all these mechanisms effectively.

Question 3

Question: What is the global prevalence of neuropathic pain, and why is it significant?

Answer 3

Answer: Neuropathic pain affects approximately 7-10% of the global population, contributing significantly to chronic pain syndromes. The complexity in diagnosing and treating neuropathic pain increases its healthcare burden worldwide.

Question 4

Question: What mechanisms lead to the development of chronic pain?

Answer 4

Answer: Chronic pain can arise due to:

Nociceptive factors: Inflammatory cytokines and persistent nociceptor activity.

Neuropathic factors: Direct damage to the nervous system.

Nociplastic factors: Dysregulation in pain modulation systems without clear nociceptive or neuropathic causes.

Question 5

Question: What is the diagnostic tree for neuropathic pain?

Answer 5

Answer: History: Neurological lesion or disease, and pain distribution neuroanatomically plausible.

Examination: Sensory signs associated with pain in the same neuroanatomical distribution.

Confirmatory tests: Diagnostic confirmation of lesion/disease affecting the somatosensory system leads to definite neuropathic pain diagnosis.

Question 6

Question: What are the key components of QST used in diagnosing neuropathic pain?

Answer 6

Answer: Thermal detection thresholds (heat/cold sensitivity).

Mechanical detection thresholds (sensitivity to punctate stimuli or blunt pressure).

Pain thresholds (hyperalgesia vs hypoalgesia).

Question 7

Question: How is hyperalgesia presented in patients with postherpetic neuralgia?

Answer 7

Answer: In postherpetic neuralgia:

Mechanical hyperalgesia is present in 78% of patients (brush, pin prick, blunt pressure).

Thermal hyperalgesia affects 40% (cold, heat, or both).

Question 8

Question: What are the key multi-level, multi-cellular mechanisms in neuropathic pain?

Answer 8

Answer: Peripheral immune cells activate sensory neurons.
Sensory signals travel to the dorsal root ganglia (DRG), then to microglia in the spinal cord.
This leads to central sensitization involving thalamus, insula, and medial prefrontal cortex.

Question 9

Question: What is central sensitization, and how does it contribute to neuropathic pain?

Answer 9

Answer: Central sensitization refers to increased responsiveness of nociceptors in the dorsal horn neurons to normal or sub-threshold stimuli. This leads to persistent pain, even after the initial injury has healed.

Question 10

Question: What happens in spinal networks when inhibition is lost?

Answer 10

Answer: In nerve injury, touch-sensitive neurons can misinterpret touch as pain due to loss of inhibition from PKCγ neurons. When inhibitory neurons (e.g., parvalbumin neurons) are activated, pain can be alleviated.

Question 11

Question: How do top-down mechanisms from the brainstem modulate neuropathic pain?

Answer 11

Answer: Noradrenaline from the brainstem inhibits pain via α2-adrenergic receptors (a2AR).

Serotonin can both inhibit and facilitate pain through different receptor subtypes (e.g., 5HT2/3R).

Question 12

Question: What is peripheral sensitization, and how does it occur?

Answer 12

Answer: Peripheral sensitization is increased sensitivity of nociceptors to stimuli due to inflammatory factors such as IL-1β, 5-HT, NGF, and IL-6. This sensitization lowers the threshold for pain signals at the periphery.

Question 13

Question: What is spontaneous activity in neuropathic pain, and how is it visualized?

Answer 13

Answer: Spontaneous activity refers to ongoing firing of neurons without external stimuli. It can be visualized via calcium imaging in sensory ganglia, which shows hyperactivity in neurons after nerve injury.

Question 14

Question: What is the sequence of events from peripheral injury to brain involvement in neuropathic pain?

Answer 14

Answer: The sequence is:

Peripheral immune activation affecting sensory neurons.

Signal transmission to DRG and spinal cord microglia.

Pain modulation in higher centers like the thalamus, insula, and medial prefrontal cortex.

Question 15

Question: What is the role of persistent peripheral drive in neuropathic pain, and how does its removal affect patients?

Answer 15

Answer: Persistent peripheral drive continues to send pain signals despite injury resolution. Removing it (e.g., via nerve block or surgery) can significantly reduce or eliminate pain in conditions like post-surgical pain and radiculopathy.

Question 16

Question: How does neuropathic pain manifest in brain connectivity?

Answer 16

Answer: Altered connectivity between the periaqueductal gray (PAG) and the anterior cingulate cortex (ACC) is seen in patients with neuropathic pain, showing a stronger connection during pain experiences.

Question 17

Question: Why is the treatment of neuropathic pain challenging, considering its underlying mechanisms?

Answer 17

Answer: The complexity of neuropathic pain arises from its multi-cellular and multi-level mechanisms involving both peripheral and central systems. Additionally, each patient’s experience and the exact pathways involved can vary, making standardized treatments less effective.