Pain (In Depth)

Why do we have pain?

- For tissue injury and infection, pain hypersensitivity accompanies the associated inflammation and persists for the duration of the inflammatory response - Pain encourages the patient to avoid use of the affected body part, therefore pain helps healing to occur. - However, pain can be maladaptive and pathological when the pain system is dysfunctional: The nociceptive system, genetic factors, injury to the nervous system can lead to neuropathic pain and abnormal central amplification syndromes. In such cases, pain is no longer the symptom but the disease itself.

First Pain vs. Second Pain

- Three classes of nociceptors are widely distributed in skin and deep tissues and are often coactivated. - When a hammer hits your thumb, you initially feel a sharp pain ("first pain") followed by a more prolonged aching and sometimes burning pain ("second pain"). -The fast-sharp pain is transmitted by Aδ fibers that carry information from damaged thermal and mechanical nociceptors. - The slow dull pain is transmitted by C fibers that convey signals from polymodal nociceptors

Thermal nociceptors

-Thermal nociceptors are activated by extremes in temperature, typically greater than 45°C (115°F) or less than 5°C (41°F). They are the peripheral endings of small-diameter, thinly myelinated Aδ axons that conduct action potentials at speeds of 6 to 30 m/s.

TRPV2

The TRPV2 channel is expressed predominantly in Aδ fiber terminals and is activated by very high temperatures, whereas the TRPM8 channel is activated by low temperatures and by chemicals such as menthol. - T > 52 degrees Celcius

What is Nociception?

•Nociception is the form of somatic sensation that detects noxious, potentially tissue-damaging stimuli. Pain has both a localizing somatic sensory component and an aversive emotional and motivational component.

What is the pathway of pain?

•Pain begins with peripheral nociceptors, which have their cell bodies in dorsal root ganglia (DRG) and in the trigeminal ganglia in the head; these neurons synapse, respectively, in the dorsal horn of the spinal cord or the trigeminal nucleus, the medullary extension of the dorsal horn. •Peripheral nociceptors express a set of channels, most notably transient receptor potential (TRP) channels, that are sensitive to noxious mechanical, thermal, and chemical stimuli. These neurons also express receptors for inflammatory mediators and substances released by damaged cells •Primary nociceptors release a large number of neuropeptide and nonpeptide neurotransmitters in the dorsal horn and trigeminal nucleus. These regions are important sites of integration for both ascending nociceptive information and descending antinociceptive (endogenous analgesic) influences.

Lamina V

- Lamina V contains neurons that respond to a wide variety of noxious stimuli and project to the brain stem and thalamus. These neurons receive direct inputs from Aβ and Aδ fibers and are also innervated by C fiber nociceptors because their dendrites extend into lamina II. - Neurons in lamina V also receive input from nociceptors in visceral tissues. The convergence of somatic and visceral nociceptive inputs onto individual lamina V neurons provides one explanation for a phenomenon called "referred pain," a condition in which pain from injury to a visceral tissue is perceived as originating from a region of the body surface. - Patients with myocardial infarction, for example, frequently report pain from the left arm as well as the chest. This phenomenon occurs because a single lamina V neuron receives sensory input from both regions, and thus a signal from this neuron does not inform higher brain centers about the source of the input. As a consequence, the brain often incorrectly attributes the pain to the skin, possibly because cutaneous inputs predominate

Lamina VII and VIII

- Many neurons located in laminae VII and VIII, the intermediate and ventral regions of the spinal cord, respond to noxious stimuli. - These neurons typically have complex response properties because the inputs from nociceptors to these neurons are conveyed through many intervening synapses. - Neurons in lamina VII often respond to stimulation of either side of the body, whereas most dorsal horn neurons receive unilateral input. - The activation of lamina VII neurons is therefore thought to contribute to the diffuse quality of many pain conditions.

Mechanical nociceptors

- Mechanical nociceptors are activated optimally by intense pressure applied to the skin; they too are the endings of thinly myelinated Aδ axons (same speed as above).

Nociceptors (pain receptors)

- Noxious insults activate nociceptors. - Most of these nociceptors are simply the free nerve endings of primary sensory neurons. - There are three main classes of nociceptors— thermal, mechanical, and polymodal—as well as a fourth class, termed silent nociceptors. These nociceptors have a higher threshold than do other mechanical and thermal receptors as they are normally activated by stimuli of noxious intensity, enough to cause tissue damage. - Pain can also arise as a brain or nerve injury (following a stroke or after infection). Unfortunately, pain can also arise without any cause. Pain not linked to injury is common and can be a major cause of disability and distress and typically respond less well to pharmacological agents.

Polymodal nociceptors

- Polymodal nociceptors can be activated by high intensity mechanical, chemical, or thermal (both hot and cold) stimuli. This class of nociceptors is found at the ends of small-diameter, unmyelinated C axons that conduct more slowly, at speeds less than 1.0 m/s.

TRPV1

- TRPV1, is expressed selectively by nociceptive neurons and mediates the pain producing actions of capsaicin, the active ingredient of hot peppers, and many other pungent chemicals. - The TRPV1 channel is also activated by noxious thermal stimuli, which suggests that it normally transduces the sensation of painful heat. - T > 43 degrees Celcius - In addition, TRPV1-mediated membrane currents are enhanced by a reduction in pH, a characteristic of the chemical milieu of inflammation.

Nociceptive Afferent Fiber Pathway

- The cell bodies of spinal nociceptive afferent fibers are found in the dorsal root ganglion neurons (or trigeminal ganglia). - The fibers enter the spinal cord via the dorsal roots ending in the gray matter of the dorsal horn. -Most nociceptive afferents terminate in the superficial region of the dorsal horn, with the C fibers and Aδ fibers synapsing onto lamina I and II. Some Aδ fibers synapse in lamina V. These neurons then send projections to the brain.

How does Noxious stimuli depolarize the bare nerve endings of afferent axons to generate action potentials that are propagated centrally?

- The membrane of the nociceptor contains receptors that convert the thermal, mechanical, or chemical energy of noxious stimuli into a depolarizing electrical potential. - One such protein is a member of a large family of so-called transient receptor potential (TRP) ion channels. - This receptor-channel, TRPV1, is expressed selectively by nociceptive neurons and mediates the pain producing actions of capsaicin, the active ingredient of hot peppers, and many other pungent chemicals.

Summary: Nociceptor receptors that convert the thermal, mechanical, or chemical energy of noxious stimuli into a depolarizing electrical potential.

- There is a large family of so-called transient receptor potential (TRP) ion channels involved in pain - TRPV1, is expressed selectively by nociceptive neurons and mediates the pain producing actions of capsaicin, the active ingredient of hot peppers, and many other pungent chemicals. - The TRPV1 channel is also activated by noxious thermal stimuli, which suggests that it normally transduces the sensation of painful heat. - In addition, TRPV1-mediated membrane currents are enhanced by a reduction in pH, a characteristic of the chemical milieu of inflammation. - Additional members of the TRP channel family are expressed by nociceptive neurons, and the variety of TRP channels in nociceptors is thought to underlie the perception of a wide range of temperatures from extreme cold to intense heat. - The TRPV2 channel is expressed predominantly in Aδ fiber terminals and is activated by very high temperatures, whereas the TRPM8 channel is activated by low temperatures and by chemicals such as menthol. - In addition to this constellation of TRP channels, other receptors and ion channels that participate in the transduction of peripheral stimuli are expressed in nociceptive sensory endings. - Nociceptors selectively express tetrodotoxin-resistant Na+ channels. One Na+ channel (NaV1.7) plays a key role in the perception of pain in humans, as revealed by the rare pain-insensitive individuals who possess mutations in the corresponding gene. - One class of mutations inactivates the NaV1.7 channel and results in a complete inability to sense pain. But in all other respects these individuals are healthy and exhibit normal sensory responses to touch, mild temperature, proprioception, tickle, and pressure. - A second class of mutations in the NaV1.7 gene changes the inactivation kinetics of this channel; individuals with these mutations exhibit an inherited condition called paroxysmal extreme pain disorder, characterized by rectal, ocular, and submandibular pain. - Nociceptors also express an ionotropic purinergic receptor, P2X, that is activated by adenosine triphosphate (ATP) released from peripheral cells after tissue damage, as well as a metabotropic P2Y receptor. - In addition, they express members of the Mas-related G protein-coupled receptor (Mrg) family, which are activated by peptide ligands and serve to sensitize nociceptors to other chemicals released in their local environment. These receptors and channels provide attractive targets for the development of drugs with actions selective for nociceptive sensory neurons.

Neuropeptides released by Nociceptive Sensory Neurons

- These peptides include substance P, calcitonin gene-related peptide (CGRP), somatostatin, and galanin. - The non-myelinated afferent neurons contain neuropeptides, particularly substance P and calcitonin gene-related peptide (CGRP). -These are mediators at both the central and peripheral terminals and play an important role in pain.

Aδ fibers vs. C fibers (nociceptive fibers)

Aδ fibers - Diameter: 2-5 um - Conduction Velocity: 6-30 m/s - Thinly myelinated - Time to Conduct 1m: 0.05 s - High-threshold mechanoreceptors, mechanothermal receptors - Blocked by: pressure C fibers - Diameter: 0.2-5 um - Conduction Velocity: 0.5-2 m/s - Unmyelinated - Time to Conduct 1m: 2.0 s - Polymodal - Blocked by: low doses of local anesthetics AB fibers - non-nociceptive

What neurotransmitters do Nociceptive sensory neurons release?

Nociceptive sensory neurons that activate neurons in the dorsal horn of the spinal cord release two major classes of neurotransmitters: - Glutamate is the primary neurotransmitter of all primary sensory neurons, regardless of sensory modality. - Neuropeptides are released as co-transmitters by many nociceptors with unmyelinated axons.

High-impact chronic pain

Pain severe enough that it frequently limits life or work activities

What is Sensitization and How does it relate to Chronic Pain?

Sensitization is a clinically significant process in which nociceptors in an area extending beyond a tissue injury exhibit decreased thresholds for activation. Sensitization can be initiated by inflammatory mediators such as prostaglandins and leukotrienes. •Damage to neurons in nociceptive pathways can lead to severe chronic pain syndromes, termed neuropathic pain. •Plasticity within the dorsal horn and trigeminal nucleus, termed central sensitization, may be key in the initiation of chronic pain syndromes by increasing the excitability of neurons in nociceptive pathways. Numerous mechanisms have been implicated in central sensitization, including plasticity mediated by NMDA glutamate receptors. •Opiate drugs selectively suppress nociception, but not other sensory modalities, by binding to endogenous opioid receptors in descending analgesic pathways. They are the most potent analgesic compounds known, but their chronic use is limited by tolerance to their analgesic effects and by risk for addiction. •Nonsteroidal anti-inflammatory drugs (NSAIDs), which are more weakly analgesic compared with opiates, act by blocking prostaglandin-mediated sensitization, specifically by inhibiting the enzyme cyclooxygenase that is required for the synthesis of prostaglandins from arachidonic acid. •Several other medications are used to treat chronic pain syndromes, including combined serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants and compounds (eg, gabapentin, pregabalin) that inhibit certain voltage-gated Ca2+ channels.