Peripheral Nociception

Question 1

Where are the cell body of axons of peripheral nerve fibres located?

Answer 1

They are in the dorsal root ganglia, located a few millimetres away from the spinal cord.

Question 2

What are the 3 types of noxious stimuli?

Answer 2

1.Supra-threshold mechanical stimuli
2. Chemical stimuli
3. Thermal energy

These stimuli act upon specialised ion channels (see notes) to produce pain. These are the only three types of stimuli that can produce pain. So since nociceptors respond to mechanical, chemical and thermal energies, we refer to them as polymodal receptors.

Question 3

What are pain sensors in the skin?

Answer 3

Pain sensors are free nerve endings that lie near the epidermis, above sensory units like Pacinian corpuscles (which detect vibration) and Merkel discs (which detect pressure). These free nerve endings are not very sophisticated but are essential for pain perception. They detect damage and relay pain signals to the central nervous system

Question 4

What role do ion channels play in nociception?

Answer 4

Free nerve endings are not the ultimate nociceptors; it’s the ion channels on the surface of these endings that detect harmful stimuli. Ion channels such as TRP channels respond to mechanical, thermal, or chemical stimuli, making these nerve endings sensitive to noxious events.

Question 5

What is the role of the dorsal root ganglion (DRG) in nociception?

Answer 5

The DRG synthesizes proteins, including ion channels, which are transported along the axon to the free nerve endings. This process determines the sensitivity of nociceptors to harmful stimuli. The DRG acts as a control center, regulating the type and quantity of ion channels present.

Question 6

What are the types of noxious stimuli?

Answer 6

Noxious stimuli can be categorized as mechanical (e.g., impact or pressure), chemical (e.g., tissue damage causing inflammation), or thermal (e.g., extreme temperatures). These stimuli activate nociceptors, leading to the sensation of pain.

Question 7

What are polymodal receptors?

Answer 7

Nociceptors respond to mechanical, chemical, and thermal stimuli, making them polymodal receptors capable of detecting multiple types of harmful stimuli. This polymodality allows the body to respond to various threats, including injury, heat, and toxic chemicals.

Question 8

What are TRP channels?

Answer 8

TRP (Transient Receptor Potential) channels are ion channels responsible for detecting harmful stimuli. They play a key role in nociception by opening in response to noxious stimuli, allowing ions to flow in and generate an action potential that signals pain to the central nervous system.

Question 9

What is the TRPV1 channel and its function?

Answer 9

A: TRPV1 is a type of TRP channel activated by capsaicin (a compound found in red peppers) and responds to temperatures above 43°C, leading to a sensation of burning pain. TRPV1 channels are critical for detecting thermal stimuli and chemical irritants, contributing to pain sensation.

Question 10

How do TRP channels work?

Answer 10

TRP channels open due to conformational changes in their structure when exposed to noxious stimuli, allowing positively charged ions like calcium and sodium to flow into the nerve ending, generating a signal. This influx of ions depolarizes the neuron, ultimately leading to an action potential that transmits pain information.

Question 11

What are TRPM8 and TRPA1 channels, and what do they detect?

Answer 11

TRPM8 is activated by menthol and responds to cooling temperatures (8-26°C), responsible for sensing cold and cool-related pain. TRPA1 is activated by mustard oil and temperatures below 17°C, contributing to cold pain and irritation. Both channels play distinct roles in the sensation of cold and temperature-related pain.

Question 12

How do mixed signals from TRP channels affect cold sensations?

Answer 12

Cold sensations can result from mixed signals from TRPV1 (which detects heat) and TRPM8 (which detects cooling). Depending on their activation, cold may be perceived as painful. The interaction between these channels influences how temperature is interpreted, ranging from a cooling sensation to burning pain.

Question 13

How do TRP channels contribute to pain signal summation

Answer 13

Multiple TRP channels can be activated simultaneously, resulting in transient receptor potentials that summate to produce an action potential, which travels to the spinal cord and is perceived as pain. This summation increases the likelihood of reaching the threshold needed for action potential generation.

Question 14

What did TRPV1 knockout experiments reveal about pain perception?

Answer 14

Knockout mice lacking TRPV1 channels show reduced responses to thermal pain, indicating the critical role of TRPV1 receptors in detecting heat-induced pain. These experiments demonstrate that TRPV1 is essential for the perception of high-temperature pain.

Question 15

What did the triple knockout study demonstrate?

Answer 15

Triple-knockout mice lacking TRPV1, TRPM3, and TRPA1 channels showed almost no response to thermal pain, emphasizing that these TRP channels are key players in nociception. The study highlights the importance of multiple TRP channels in pain processing.

Question 16

What is the function of the DRG?

Answer 16

The DRG contains the cell bodies of neurons that give rise to peripheral nerve axons, which end in free nerve endings. The DRG plays a critical role in processing nociceptive information, serving as the origin point for sensory neurons that transmit pain signals

Question 17

What are pseudo-unipolar neurons?

Answer 17

The DRG contains pseudo-unipolar neurons, which have one axon that branches into two: one branch extends to the spinal cord, while the other extends to the periphery, giving rise to free nerve endings. This unique structure allows for efficient transmission of sensory information from the periphery to the central nervous system.

Question 18

What types of fibers are found in the peripheral nerves?

Answer 18

Peripheral nerves contain sensory fibers (A-fibers and C-fibers) and motor fibers. A-fibers are thick, myelinated fibers that transmit pain signals rapidly, while C-fibers are thin, unmyelinated fibers that transmit pain signals more slowly. The myelination of A-fibers allows for saltatory conduction, resulting in faster signal transmission compared to C-fibers.

Question 19

What are the functions of A-delta and C-fibers?

Answer 19

A-delta fibers are responsible for transmitting quick, sharp pain (first pain), while C-fibers transmit slow, burning pain (second pain). A-delta fibers are myelinated, allowing for faster transmission, whereas C-fibers transmit dull, aching pain due to their unmyelinated nature.

Question 20

How do A-beta fibers contribute to pain modulation

Answer 20

A-beta fibers typically transmit tactile information and oppose pain by activating inhibitory pathways. However, under pathological conditions (e.g., secondary hyperalgesia), A-beta fibers can also transmit pain signals, contributing to increased pain sensitivity in injured or inflamed areas

Question 21

What are the characteristics of C-fibers?

Answer 21

C-fibers are mechano-heat nociceptors responsible for burning pain, warmth, and affective touch. They have large receptive fields, making it difficult to localize the pain precisely. C-fibers are also involved in chronic pain conditions, as their slow conduction contributes to prolonged pain sensations.

Question 22

How do C-fibers respond to stimulus intensity?

Answer 22

C-fibers fire action potentials in response to escalating heat, showing a nearly linear relationship between stimulus intensity and firing rate. This relationship is crucial for understanding how pain intensity correlates with the strength of a noxious stimulus, particularly in thermal pain perception.

Question 23

What are the types of A-delta fibers and their functions?

Answer 23

There are two types of A-delta fibers: Type 1 fibers have longer response latencies and are less adaptive, while Type 2 fibers adapt quickly and respond to short-lasting stimuli, typically found on hairy skin. Type 1 fibers are better at detecting sustained noxious stimuli, whereas Type 2 fibers are more responsive to sudden changes.

Question 24

How do A-delta and C-fibers contribute to pain perception?

Answer 24

First pain, mediated by A-delta fibers, is a sharp and brief sensation. Second pain, mediated by C-fibers, is a slower, burning sensation. Both types of pain contribute to the overall perception of a painful event, with first pain providing a warning signal and second pain contributing to the lingering discomfort.

Question 25

What is hyperalgesia?

Answer 25

Hyperalgesia refers to increased sensitivity to pain, where even mild stimuli can cause intense pain. This occurs due to changes in peripheral nociceptors, often following tissue damage or inflammation. Hyperalgesia can be a protective mechanism but may become maladaptive in chronic pain conditions.

Question 26

What is the difference between primary and secondary hyperalgesia?

Answer 26

Primary hyperalgesia occurs at the site of injury and involves increased sensitivity of nociceptors, while secondary hyperalgesia affects surrounding uninjured areas due to central sensitization in the spinal cord. Primary hyperalgesia is driven by peripheral mechanisms, whereas secondary hyperalgesia is associated with changes in the central nervous system.

Question 27

What are the mechanisms of primary hyperalgesia?

Answer 27

Primary hyperalgesia is caused by sensitization of nociceptors, upregulation of TRP channels via nerve growth factor (NGF), and activation of silent nociceptors, which become responsive during inflammation. These mechanisms increase the excitability of nociceptors, leading to enhanced pain perception.

Question 28

What chemical agents contribute to hyperalgesia?

Answer 28

Bradykinin, histamine, serotonin, substance P, leukotrienes, and prostaglandins are chemical agents released from damaged tissues that sensitize nociceptors, contributing to primary hyperalgesia. These agents increase ion channel activity, lowering the threshold for activation and making nociceptors more responsive to stimuli.

Question 29

How can hyperalgesia be modulated?

Answer 29

Pain modulation can occur through substances like opioids (which reduce neurotransmitter release such as substance P and glutamate and hyperpolarize neurons), cannabinoids (which bind to CB1 and CB2 receptors and reduce excitability), and somatostatin (which inhibits calcium inflow in TRP channels). These modulatory substances help reduce the intensity of hyperalgesia and provide relief from pain.