Neuropathic Pain Flashcards
What are the two main categories of analgesics used for pain management?
- NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
- Opioids
What are the primary types of sensory nerve fibers in the peripheral nervous system?
- Abeta fibers (large, innervate sensory mechanoreceptors)
- Adelta fibers (thinly myelinated)
- Unmyelinated C fibers (thermoreceptors/nociceptors)
Describe the path of nociceptor activity from peripheral nerves to the brain.
- Nociceptor activity travels through pathways in the spinal cord, brain stem, and terminates in various cortical areas of the brain
What are the clinical challenges in pain management?
- Chronic pain is a widespread unmet need
- Medications often offer inadequate pain control
What is the pain stimulus and mechanism for nociceptive pain?
- Pain Stimulus: Tissue damage
- Mechanism: Activation of nociceptors
What is the pain stimulus and mechanism for inflammatory pain?
- Pain Stimulus: Inflammatory mediators
- Mechanism: Involves both peripheral and central sensitization
What is the pain stimulus and mechanism for neuropathic pain?
- Pain Stimulus: Nerve injury
- Mechanism: Includes ectopic activity, neuro-immune interactions, and central sensitization
What is the pain stimulus and mechanism for dysfunctional pain?
Pain Stimulus: Not known
Mechanism: Not known
What is the characteristic feature of dysfunctional pain?
-Characteristic Feature: Dysfunction in the central organization generating pain signals in the absence of tissue damage in the periphery.
How is neuropathic pain defined?
- Pain that arises as a direct consequence of a lesion or disease affecting the somatosensory system
What are the various types of receptors in the somatosensory system?
Thermoreceptors, photoreceptors, mechanoreceptors, and chemoreceptors.
Name some examples of conditions or pathologies that can lead to neuropathic pain.
-HIV infection
- metabolic/nutritional issues (e.g., diabetic and alcoholic neuropathy),
- neurotoxicity (e.g., from drugs like cisplatin and taxol)
- traumatic injury (e.g., surgical damage)
- central lesions (e.g., spinal cord injury & stroke)
What is a common issue in neuropathic pain, especially in conditions like diabetes?
-Spontaneous pain
- which can be persistent and exist even when patients cannot sense direct tactile stimulation.
What is postherpetic neuralgia, and what is its association with varicella-zoster virus?
- It’s chronic neuropathic pain that persists in some individuals who have had shingles, caused by the varicella-zoster virus.
- This virus lives in the DRG, becoming activated in the DRG, and can lead to pain related to damage to central fibers
How are animal models of diabetic neuropathy typically induced, and what is their purpose?
- Induction of Diabetic Neuropathy: Animal models of diabetic neuropathy are often induced by using streptozotocin (STZ), a drug toxic to the insulin-producing beta cells in the pancreas.
- Purpose: replicate the neuropathic pain associated with diabetes & study potential treatments
What are some common models for studying neuropathic pain in animals, especially involving damage to peripheral nerves?
- Common Models:
Inducing injury to large peripheral nerves like the sciatic nerve. - Examples include loosely tying sutures around the nerve to cause swelling and partial nerve degeneration.
- Other models include the chronic restriction injury, where half of the sciatic nerve is affected.
What is a common model for studying neuropathic pain that doesn’t damage the sciatic nerve itself but the roots connecting it to the dorsal root, and what advantage does this model offer?
- One common model involves damaging the roots that connect the sciatic nerve to DRG rather than the sciatic nerve itself.
- Advantage: In this model, all the damaged cells are located in 1 DRG, which allows for separate study of these cells.
- In contrast, other models result in scattered damaged nerve fibers throughout the nerve, making it harder to isolate & study them.
What happens to damaged nerve fibers in neuropathic pain, particularly in terms of gene expression?
- Phenotypic Shift: Damaged nerve fibers undergo a dramatic shift in their phenotype.
- Gene Expression: thousands of genes dysregulated following nerve injury & this is likely to impact nerve’s function.
- Ectopic Activity: Nerve fibers disconnected from peripheral targets may generate spontaneous AP which CNS interprets as pain
In neuropathic pain, how does the processing of somatosensory information in the spinal cord change, and are the mechanisms well understood?
- Processing Amplification: In neuropathic models, the processing of somatosensory info in spinal cord is amplified by several mechanisms
- Mechanism Variability: It’s not entirely clear which mechanisms are most important & there may be variations in their importance in different categories of patients
What happens to nerve fibers in damaged nerves, and how does this relate to neuropathic pain?
- Nerve Damage: In damaged nerves, Wallerian degeneration occurs, where the nerve fibers undergo degeneration.
- Pain Connection: This partial innervation of target tissue resulting from Wallerian degeneration believed to contribute to neuropathic pain.
note: Many factors released during Wallerian degeneration, which can act on the spared nerve fibers and potentially drive neuropathic pain
What is a Remak bundle?
- consists of C fibers grouped together, where unmyelinated Schwann cells bundle axons closely by surrounding them, keeping them from touching each other
how does a Remak bundle change in neuropathic pain?
- these bundles are reduced in size due to axon degeneration
- the remaining axons are located in partially deinnervated Schwann cells, which respond to nerve damage by releasing numerous injury factors
- remaining fibers are exposed to these factors, potentially leading to abnormal activity
How does nerve injury impact gene expression?
- Nerve injury can lead to the dysregulation of thousands of genes
What are the functional consequences of gene expression changes after nerve injury?
- Nerve injury-induced gene expression changes can result in production of novel NTs & disrupt genes related to nociceptive properties
How does nerve injury affect opioid receptors in neuropathic pain patients?
- can lead to downregulation of opioid receptors that are usually present on C fibers
How does the onset of activity relate to altered behaviour in neuropathic pain?
- onset of spontaneous activity in nerve fibers correlates with onset of altered behavior in neuropathic pain
what happens to both damaged and non-damaged neurons in neuropathic pain?
- Both damaged and non-damaged neurons display ectopic (abnormal) activity in neuropathic pain
What is a distinguishing feature of neuropathic pain compared to other types of pain?
- isolated neurons themselves become sources of ectopic firing
(has been demonstrated in humans by applying a needle into the nerve to measure the activity)
How does blocking spontaneous activity affect neuropathic pain behavior?
- reverses neuropathic pain behaviour, providing a potential therapeutic approach
What is the role of Nav1.8 Na channel in neuropathic pain?
- found only in nociceptors
- suggested to play a role in neuropathic pain
How was the role of Nav1.8 Na channel initially studied, and what were the results?
- antisense sequences used to target the Nav1.8 Na channel
- & it appeared to have a role in neuropathic behaviour recovery
What did the discovery of a Nav1.8 knockout (KO) animal reveal about its role in neuropathic pain?
- found that a Nav1.8 KO animal could still display neuropathic pain,
(casting doubt on channel’s exclusive involvement)
What other Na channel was upregulated in neuropathic pain?
- Nav1.3 Na channel
- potentially to increase excitability of damaged nerve fiber
How does the presence of a Nav1.3 KO mouse impact neuropathic pain?
- Even though Nav1.3 was upregulated, presence of a Nav1.3 KO mouse also developing neuropathic pain …suggests that this channel may not be the sole cause
What is another possible mechanism for neuropathic pain related to nerve excitability?
- Downregulation of K+ channels, which hyperpolarize and dampen neuronal excitability, may contribute to neuropathic pain.
- Many K+ channels are downregulated in neuropathic pain models
How did a study involving the KCNS1 gene support the role of K channel downregulation in neuropathic pain?
- Individuals with mutation in the KCNS1 gene, which encodes a K channel are more susceptible to neuropathic pain
- and downregulation of K channels can induce a neuropathic pain state (Costigan et al 2010).
What are some potential issues associated with studying neuropathic pain and these changes in connectivity?
- Statistical power could be an issue in studies related to neuropathic pain and its connectivity changes
What is the debate between peripheral and central causes of neuropathic pain?
- debate regarding whether neuropathic pain primarily arises from peripheral or central causes
- however, noted that persistent peripheral drive is common in neuropathic pain
