Chapter 13: Pain and Temperature (NE 203) (copy)

nociceptors

• unspecialized, nonspecific nerve endings that transmit a variety of stimuli and translate them into afferent action potentials

• two kinds of slowly transmitting afferent fibers:

  • Aδ lightly myelinated axons.

  • C unmyelinated axons, small diameter.

• Pain is transmitted only when strength of stimulus is high

the neuronal basis of pain

(B) in the painful stimulus range, the axons of non-nocieptive thermoreceptors, the number and frequency of action potential discharges in the nociceptive axon, continue to increase

two categories of pain

• faster conducting sharp first pain carried by Aδ fibers

• delayed, broadly acting, dull second pain carried by C fibers which respond to all types of nociceptive stimuli

two types of Aδ fibers

• type 1: high heat thresholds, respond to immediate potentially dangerous stimuli

• type 2: low heat threshold, high threshold for mechanical stimulation

Nociceptors are

• primary sensory afferents that initiate the sensation of pain.

What types of endings do nociceptors possess?

• Peripheral nociceptive axons terminate in morphologically unspecialized free nerve endings.

How do first pain and second pain differ?

• In general, Aδ nociceptive fibers are responsible for first pain and C nociceptive fibers are responsible for the duller, longer-lasting second pain.

vanilloid receptor

• member of the transient receptor potential (TRP) family

• found on the endings of Aδ and C fibers

transient receptor potential (TRP)

transmembrane cation selective channels that mediate depolarization in response primarily to various sensory stimuli

TRPM8

mediates high concentration of methanol, which can be painful

Peizo 2

rapidly adapting ion channel

ASIC (acid sensing ion channel)

sensitive ti muscle and cardiac pain and to changes in pH

capsaicin figure

• activates TRP1, whose endogenous ligand is anandamide and temperature

• found in chili peppers, habanero, etc

• is an irritant when applied to mucus membranes of the mouth and when injected subcutaneously

• repeated administration → desensitization

What are TRP channels?

• Transient receptor potential (TRP) channels are a group of ion channels that are sensitive to different ranges of heat, cold, and chemical stimuli.

What are ASIC3 channels?

• Expressed in nociceptors, including neurons that innervate skeletal and cardiac muscle, ASIC3 channels are thought to be responsible for the muscle or cardiac pain that results from changes in pH associated with ischemia

What happens when the NAV1.7 gene (known as SCN9A in humans) does not function properly?

• A loss of this channel's function result in an inability to detect noxious stimulation, while mutations leading to hyperexcitability of the channel are associated with pain disorders that cause intense burning sensations.

dorsolateral tract of lissauer

ascending and descending branches of incoming afferent axons entering the dorsal horn

anterolateral system (AL)

formed from 2nd order neuronal axons in the dorsal horn laminae I and IV (wide dynamic range neurons) ascends carrying pain, temperature and crude touch information to somatosensory cortex via the thalamus

wide dynamic range neurons

multimodal lamina V neurons that receive converging inputs from nociceptive and non-nociceptive afferents, a quality which makes them a likely substrate for refereed pain

dorsal column medial leminscal system (DMCL)

carries mechanical stimuli: touch, pressure, vibration, proprioception

the anterolateral system

nociceptive and mechanosesnory pathways

referred pain figure

• visceral (internal) pain is transmitted via dorsal horn neurons that also convey cutaneous pain

• a point of confusion about where the visceral pain originates

• a common example: anginal pain arising because of inadequate blood flow in the heart is referred to the left arm and hand

• another common example: gall bladder pain referred to the scapular region

anterolateral system

sensory discriminative and affective motivational

sensory discriminitive

• mediaytes location, intensity, quality of the noxious stimulus

• conveyed by the anterior spinothalamic tract → ventral posterior lateral nucleus of thalamus

affective motivational

unpleasant feelings, fear and anxiety, autonomic reactions that accompany noxious responses, such as the sympathetic nervous system

pain matrix

• extensive network of forebrain regions enabling one to experience the full range of pain

• consists of the: ventral posterior medial thalamus, somatosensory, insular, and anterior cingulate cotices

face pain

• originates in the trigeminal (V) ganglion and from other ganglion associated with cranial nerves VII, IX, and X

• climbs the trigeminothalamic tract → ventral posterior medial thalamus

In which spinal cord laminae do most C- and Aδ-nociceptive neurons form synaptic connections?

• The superficial laminae I and II

What are wide-dynamic range neurons?

• Multi-modal spinal cord interneurons that receive converging inputs from nociceptive and non-nociceptive afferents.

How do the sites of decussation differ between the anterolateral and dorsal column–medial lemniscal pathways?

• The first-order and projection neurons for the dorsal column–medial lemniscal system ascend in the ipsilateral dorsal columns to the dorsal column nuclei. The axons of neurons in the dorsal column nuclei then cross the midline and ascend to the contralateral thalamus. In contrast, the crossing point for information conveyed by the anterolateral system lies within the spinal cord.

How would pain and touch sensitivity change in an individual with a unilateral spinal cord lesion?

• Loss of sensation of touch, pressure, vibration, and proprioception on the side of the body ipsilateral to the lesion, and deficits of pain and temperature perception on the contralateral side of the body.

anterolateral system cont’d

itch → histamine → histamine receptors (HR1) synapse with lamina I neurons containing gastrin releasing peptide (GRP) excites pruriceptive neurons that ascend in the spinothalamic tracts → transmit the perception of itch to thalamus, primary and second somatosensory, anterior cingulate and prefrontal cortices

pruriceptive

type of itch that originates in the skin when peripheral sensory nerve endings are activated by physical damage, insect bites, dry skin, or inflammatory chemical mediators

lamina I

• contain several distinct classes of modality specific neurons that convey both noxious and innocuous sensory information to the anterolateral system

• ex: sharp (first) pain, burning (second) pain, innocuous warmth and cold

• distinguishes interoception from exteroception

interoception

the sense of the internal state of the organism

exteroception

the modality of touch and pressure

other modalities mediated by the anterloateral system

• afferents from internal organs: unmyelinated small diameter C fibers and lightly myelinated medium diameter Aδ fibers

dorsal root ganglion neruons

perceive conscious and unconscious sensations of the GI tract, including pain, stretch and mechanical forces and microbial make up

Other than pain, what modalities are transmitted by the anterolateral system?

• Non-discriminative (affective) touch, innocuous temperature, and itch

Which ion channels allow for sensing warm and cool temperatures?

• Warm-sensing fibers express TRPV3 and TRPV4, while cool-sensing fibers express TRPM8

sensitization

• peripheral mechanisms and treatments

• protect the injured area, promote healing, and ward off infection

hyperalgesia

• perception that pain is worse than it would normally be considered to be

• can be initiated and maintained by calcitonin gene related peptide (CGRP)

peripheral sensitization

activated nociceptors stimulate the influx of non-neuronal cells (immune cells), neuropeptides and neurotransmitters, lipids, cytokines, and growth factors, all of which contribute to inflammation

nonsteroid ant inflammatory drugs (NSAIDs)

can be used to treat pain sensitivity: inhibits cyclooxygenase → inhibits prostaglandin synthesis → reduction in inflammation and pain

inflammatory response to tissue damage

• substances released by damage tissues augment the response of nociceptive neurons

• electrical activation of nociceptors causes the release of peptides and neurotransmitters that further contribute to the inflammatory response

allodynia

• induction of pain by a normally innocuous stimulus

• caused by inadvertent stimulation of 2nd order neurons in the dorsal horn that normally receive nociceptive inputs to give rise to a sensation of pain

windup

• progressive increase in the discharge rate of forsal horn neurons in response to low frequency activation of nociceptive afferents

• perceived pain increases with each successive presentation of stimulus

• lasts as long as the stimulation does and results from summation of slow synaptic potentials

central mechanisms and treatments

• LTP like enhancement of postsynaptic potentials

• CGRP signalling

• microglia and astrocytes and non-immune cells contribute to inflammation

placebo effect

• a beneficial effect as a result of a pharmacologically inert “remedy”

• in postoperative patients can be blocked by naloxone

• leads to activation of opioid receptors in cortical and subcortical brain areas

the physiological basis of pain modulation

• electrical or pharmacological stimulation of certain midbrain areas provides pain relief

• descending brainstem regions that regulate nociceptive transmission to spinal cord include

  • parabrachial nucleus

  • dorsal rphe

  • locus coeruleus

  • reticular

• wide variety of neurotransmitters used

• mediate analgesic effects of the periaqueductal gray (PAG)

• descending projections to the dorsal horn balance excitatory and inhibitory neurons, plus the synaptic terminals of other descending pathways, to determine the efficiency of nociceptive transmission

Which is an example of hyperalgesia?

• The increased sensitivity to temperature on the skin that occurs after sunburn

How do peripheral and central sensitization mechanisms differ?

• Peripheral sensitization refers to the interaction of nociceptors with substances released from activated nociceptors and/or from non-neuronal cells that reside in, or migrate to, a damaged area of tissue. Central sensitization refers to the activity-dependent increase in the excitability of neurons in the dorsal horn of the spinal cord following high levels of activity in nociceptive afferents.

What did Ronald Melzack and Patrick Wall's ''gate control theory of pain'' propose?

• The flow of nociceptive information through the spinal cord is modulated by concomitant activation of low-threshold mechanoreceptor neurons.

descending systems modulate the transmission of ascending pain signals

• interactions between mechanoreceptor afferents and dorsal neural circuits modulate the transmission of nociceptive information to higher centers

melzack and wall’s gate control theory of pain

concomitant activation of low threshold mechanoreceptors can mitigate ascending nociceptive signals

endogenous opioids

• receptors located in the PAG

• 3 classes

  • enkaphalins: found in rostral ventral medulla

  • dynorphines: found in rostral ventral medulla

  • endorphins

• modulate nociceptive transmission at the 1st synapse between nociceptive afferents and projection neurons in dorsal horn

endocannibinoids

• exogenous administration suppresses nociceptive neurons in dorsal horn

• decrease release of GABA and glutamate

• CB1 antagonists can block the analgesic effects caused by eletrical stimulation of the PAG

• increased exposure to noxious stimuli → increased release of endocannibinoids in PAG

• activate CB1 receptors → increaed microglia activation → decreased activation of glial cells → decreased pain transmission