Pain Test

CLOSES GATES

"A" BETA

___have important analgesic actions of spinal cord

**ASA, NSAIDS

Activation of N-methyl-D-aspirate (NMDA) and non-NMDA receptor mechanisms NMDA activation and Increased intracellular calcium through channels to produce arachidoic acid (AA) and induces formation of prostaglandin

**Glutamate asparate - impt. For wind up

Describes acute changes in the responsiveness of second order neurons following high intensity or prolonged stimuli such as with nonneuronal tissue injury and subsequent inflammation

*Central Sensitization**

*Wide-dynamic-range neurons* respond to what types of stimuli and where are they located?

*mechanical and noxious stimuli*Location: mainly in Rexed's laminae I, II and *V*.

Wide dynamic range (WDR) second order neurons

-also receive non-noxious afferent input from A-Beta, A-Delta, and C fibers -Most prevalent cell type in dorsal horn Most abundant in lamina V (but in I, II and V) With repeated stimulation these neurons increase their firing rate even with the same stimulus intensity Have large receptive fields compared to nociceptive-specific neurons (large range of intensity of stimulation)

what are the three mechanism responsible for central modulation?

1. *Wind-up and sensitization of second order neurons*. WDR neurons increase their frequency of discharge with the same repetitive stimuli and exhibit prolonged discharge, even after afferent C fiber input has stopped. 2. *Receptor field expansion.* Dorsal neurons increase their receptive fields such as adjacent neurons become responsive to stimuli (whether noxious or not) to which they were previously unresponsive. 3. *Hyperexcitability of flexion reflexes* -observed both ipsilaterally and contralaterally

who devised the "Gate Theory"?

1965 Melzack and Wall devised the Gate Control Theory.

OPENS GATES

A DELTA C FIBERS

In acute pain, glutamate activates ___ receptors on ___&___channels

AMPA; Na+ and K+

___ also modulates nociceptive activity in the dorsal horn.

Adenosine

Modulation occurs:

At nociceptor In the spinal cord In supraspinal structures **Modulation can inhibit (suppress) or facilitate (aggravate pain)***

In periphery many of the substances (alogens) that can sensitize nociceptors as a result of inflammation or tissue injury are:

Bradykinin Histamine Lactic acid Serotonin (5-hydroxytryptamine or 5-HT) Hydrogen and Potassium ions Substance P (p means pain) Some prostaglandins These substances may decrease nociceptor thresholds and act as sensitizers to pain

Changes in excitability occur in *second order neurons* when *repetitive or prolonged* high intensity input is received from primary afferent C-fibers. One of these changes in excitability is termed ___

C-fiber "wind-up"

Increased activity via the spinothalamic tract to the brain, mediated by glutamate receptors and substance P is termed -

CENTRAL MODULATION

Persists Past 1 to 6 Months Can be: Neuropathic (next slide) Nociceptive or combination of both

CHRONIC PAIN

"Peripheral" Modulation Primary Hyperalgesia Sensitation of nociceptors result in:

Decrease in threshold Increase in frequency response to the same stimulus intensity Decrease in response latency Spontaneous firing even after cessation of stimulus (after discharges)

Neuropeptides and excitatory amino acids function as neurotransmitters for afferent neurons, what are they?

Excitatory amino acid: Glutamate Most important peptides: substance P (sP) Calcitonin gene-related peptide (CGRP)

what are the two components of noxious stimuli?

Fast, sharp, and well localized sensation (first pain) conducted by short latency by A-delta (pinprick) Duller, slower onset, poorly localized (second pain) conducted by C fibers.

Neurochemical mediators of central sensitization substances trigger changes in membrane excitability by interacting with___ receptors on neurons activating intracellular 2nd messenger. This pathway increases____

G protein- coupled membrane; Calcium

what are the 2 subtypes of GABA receptors?

GABA-A, and GABA-B,

what are the roles of Glutamate and aspartate in wind-up and the induction and maintenance of central sensitization?

Glutamate and aspartate play important roles in wind-up, via activation of N-methyl-D-aspartate (NMDA) and other receptor mechanisms, and in the induction and maintenance of central sensitization.

What are the amino acids that function as inhibitory neurotransmitters and likely play an important role in segmental inhibition of pain in the spinal cord.

Glycine and γ-aminobutyric acid (GABA)

what Rexed's leminae make up the dorsal horn?

I - VI

Most nociceptive C fibers send collateral to, or terminate on second-order neurons in what laminas?

I, II and to lesser degree V

Nociceptive A-delta synapse mainly in what lamina?

I, V, and lesser degree X

what is the Gate Theory?

It is based on the concept that only one transmission in the form of neuron depolarization can propagate through the "Gate" at a time. Thus, if larger, proprioceptive and mechanical fibers (A alpha and beta) are stimulated the smaller pain fibers (A-delta and C) will have a closed "gate" to activation.

Since endorphins and enkephalins inhibit pain by opening___channels, the closure induces opiate resistance

K+ channels

named because it is not found in lower animals) tract projects mainly to the ventral posterolateral nucleus of thalamus Carries discriminative aspects of pain- location, intensity and duration Carries pain and temperature

Lateral (neospinothalamic)

respond to pinch and pinprick

Mechanonociceptors

- named because it found in lower animals) tract projects to the medial thalamus and is responsible for ***mediating the autonomic and unpleasant emotional perceptions of pain

Medial spinothalamic (paleospinothalamic)

The maximal depolarization of the neuron by continued release of glutamate aids in releasing ___ from the ion channel, thus eliciting a response from the NMDA receptors

Mg

In acute pain, glutamate activates AMPA receptors on ____channels

Na+ and K+

Spontaneous, burning quality, lancinating, hyperpathia (hyperesthesia) Termed - DEAFFERENATION PAIN - loss of sensory input (amputation) Termed sympathetically maintained pain - sympathetic system plays a roll

Neuropathic

what are the two types of Second-Order Neurons?

Nociceptive or Wide dynamic range (WDR)

examples of neuropathic chronic pain

Peripheral neural disorders Ex. stroke, spinal cord injury, multiple sclerosis, cancer pain

most prevalent and respond to excessive pressure, extreme temperature and alogens (pain-producing substances)

Polynodal mechanoheat

Receive all afferent neural activity Represent the principal site of modulation of pain by ascending and descending neural pathways

Rexed's Leminae

responds primarily to noxious (Nociceptive) stimuli from cutaneous and deep somatic tissues

Rexed's lamina I

called substantia gelatinosa - contains many interneurons and believed to play a major role in processing and modulating nociceptive input form cutaneous nociceptors. **Where opioids work**

Rexed's lamina II

receive non-nociceptive sensory input V-visceral afferents terminate here, and to a lesser extent I, V responds to both noxious and non-noxious sensory input and receives both visceral and somatic pain fibers **convergence -referred pain)***

Rexed's lamina III & IV

called intermediolateral column and contains the cell bodies of preganglionic sympathetic neurons

Rexed's lamina VII

central convergence between somatic and visceral input

Rexed's laminas I & V

make up anterior horn

Rexed's laminas VIII & IX

examples of nociceptive chronic pain.

Rheumatoid arthritis Osteoarthritis Ex. musculoskeletal disorders, chronic visceral disorders, lesions of peripheral nerves, nerve roots, dorsal root ganglia (including diabetic neuropathy, causalgia, phantom limb pain, postherpetic neuralgia)

respond only in presence of inflammation

Silent nociceptors

Alternate Pain Pathway that ascends uncrossed to the lateral cervical nucleus, relays to contralateral thalamus Some fibers in dorsal columns are responsive to pain , ascend medially and ipsilaterally

Spinocervical tract

Alternate Pain Pathway that activate the hypothalamus and evoke emotional behavior

Spinohypothalamic and spinotelencephalic tracts

may be important in activating anti-nociceptive, descending pathways, because is has projections to periaqueductal gray

Spinomesencephalic tract

Second Order Neurons

Spinothalamic Tract/Alternate Pathways/Integration with Sympathetic and MotorSystems

Considered major pain pathway Lies anterolaterally in white matter of spinal cord

Spinothalamic Tract

An 11 amino acid peptide synthesized and released by first order neurons both peripherally and in dorsal horn sP facilitates transmission in pain pathways via NK-1 receptor activation In periphery, sP neurons send collaterals that are closely associated with blood vessels, sweat glands, hair follicles and mast cells

Substance P

how does substance P potentate transmission of pain signals from the periphery?

Substance P causes degranulation of the mast cells and, along with CGRP, also induces changes in the vascular endothelial cells. The resulting outpouring of potent inflammatory and vasodilating agents (serotonin, histamine, nitric oxide, bradykinin, and vasoactive intestinal peptide) causes edema and potentiates transmission of pain signals from the periphery

once first order neurons are in the dorsal horn, they form what synapses?

Synapse with second-order neurons May synapse with interneurons sympathetic neurons and visceral horn motor neurons

____ serves as a relay and interpretation center for some sensory impulses that reach the cerebral cortex

Thalamus

Located in thalamus Send fibers to somatosensory areas I and II in postcentral gyrus of the parietal cortex and the superior wall of the sylvian fissure Perception and discrete location of pain take place in these cortical areas

Third-Order Neurons

NMDA activation induces nitric oxide synthesis-forming nitric oxide Nitric oxide and prostaglandins facilitate release of excitatory amino-acids in spinal cords

True

Pain fibers may ascend or descend on to three spinal cord segments in Lissauer's tract before synapsing with second-order neurons in gray mater of ipsilateral dorsal horn cord then ascend on the contralateral side True or False?

True

SP Sensitizes nociceptors, degranulates histamine from mast cells and serotonin (5-HT) from platelets, is a potent vasodilator and a chemoattractant for leukocytes Innervate the viscera and send collateral fibers to paravertebral sympathetic ganglia, intense stimulation of viscera Can cause direct post ganglionic sympathetic discharge

True

Second-Order Neurons Afferent fibers enter spinal cord segregate according to size, with large, myelinated fibers becoming medial, and small, unmyelinated fibers becoming lateral. True or False?

True

The enkephalin that is released from lamina I interneurons attaches to the receptors of the nerve terminal of the C fiber afferent and inhibit that release of substance P. True or False?

True

what are the two principle nociceptors receptors and what do they respond to?

Two principle receptors High threshold mechanoreceptors (HTMs) polymodal nociceptors (PMNs) HTM respond to mechanical stimuli and have receptive field of 1 cm2 Conduct via myelinated A delta fibers at rate of 5-25 m/sec and transmit sharp pain with rapid onset PMNs respond to mechanical, thermal, and chemical irritants Conduct via unmyelinated C fibers at a rate of less than 2 m/sec and convey dull aching pain with slow onset

Noxious stimuli in noncontiguous parts of body inhibit ___neurons at other levels which may explain why pain in one part inhibits pain in another part

WDR

___ refers to neurons in the spinal cord that respond to a large range of intensity of stimulation.

Wide dynamic range

Primary hyperalgesia is mediated by release of____ from damaged tissues. histamine is released from ___, ____, & ____

alogens mast cells, basophils, and platelets

The medial division of the spinothalamic tract projects to where?

brain stem, reticular formation, medial thalamus, periaqueductal gray matter and hypothalamus

NO also stimulates the release of substance P, which by binding to NK-1 receptors in the dorsal horn membrane, triggers ___ gene expression and promotes neural remodeling and hypersensitization

c-fos

Primary afferents, at their synapse with 2nd order neurons release many substances including:

calcitonin gene-related peptide that enhances the release of glutamate from the dorsal horn substance P excitatory amino acids - glutamate and aspartate- that elicit both fast and slow response to pain

Bradykinin is released from tissue following activation of what___. Bradykinin activates free nerve endings via what specific receptors?

factor XII specific B1 and B2 receptors

After prolonged sensitization, cells in the dorsal horn release chemicals that cause action potentials to do what? Result of the dorsal root reflex, nociceptive dendrites release ___ and ___ into the peripheral tissues.

fire backwards down the nociceptors substance P; calcitonin gene-related peptide (CGRP)

Incoming pain signals trigger the release of ____ into the synaptic cleft between nociceptors and dorsal horn cells

glutamate

Incoming pain signals trigger the release of ___into the synaptic cleft between nociceptors and dorsal horn cells.

glutamate

Activation ___ fibers inhibit WDR neuron and spinothalamic tract activity

large afferent

Second-order neuron

located in the dorsal horn. arises in the gray matter. Its axon travels in an ascending tract and decussates prior to entering the thalamus

First-order

located in the dorsal root (periphery). always the sensory neuron bearing the receptor on its dendritic end. Its cell body is in a sensory ganglion

Third-order neuron

located in the thalamus. (inner chamber) Its axon passes to the somatosensory cortex where it synapses on a cortical neuron.

Believed to mediate arousal, autonomic responses and emotional and affective aspects of pain

medial division of the spinothalamic tract

secondary hyperalgesia is also referred to as what?

neurogenic inflammation

what is the function of the dorsolaterral tract?

pain modulation

Decending neurons originating in the ___&____terminate on enkephalin-releasing interneurons in Rexed's lamina II (substantia gelatinosa)

periventricular and periaqueductal gray mater

Prostaglandin are produced following tissue damage by action of what enzyme on phospholipids released from cell membranes to form ____acid.

phospholipase A2; arachnidonic

Antagonism of glycine and GABA results in what reaction?

powerful facilitation of WDR neurons and produces allodynia and hyperesthesia.

collateral fiber of the spinothalamic tract also project to the ____ and ____these are likely responsible for arousal response to pain

reticular activating system and the hypothalamus;

how does substance P contribute to central sensitization?

sP contributes to central sensitization by exerting a positive feedback effect on NMDA receptors by also removing the Mg block within the channel of NMDA receptors.

Nociceptive -specific second order neurons

serve only noxious stimuli are arranged somatotopically in lamina I and have discrete, somatic receptive fields, usually silent an respond only to high-threshold noxious stimulation

Neurochemical mediators of central sensitization include

substance P, CGRP (Calcitonin gene-related peptide) , vasoactive intestinal peptide (VIP), cholecystokinin (CCK), angiotensin, and galanin, as well as the excitatory amino acids L-glutamate and L-aspartate.

Second order neurons leaving lamina V cross to what side of spinal cord?

the opposite (contralateral) side in the spinal

Axons of second-order neurons cross the middle to the contralateral side of the spinal cord before they form the spinothalamic tract and send there fibers to where?

the thalamus, reticular formation, and nucleus raphe magnus and periaqueductal gray

secondary hyperalgesia is Manifested by:

triple response Red flush (flare) Local tissue edema Sensitization to noxious stimuli Due to sP ( and probably CGRP)

Somatic and visceral afferents fully integrated with skeletal motor and sympathetic systems in spinal cord, brainstem and higher centers true or false?

true

Some fibers of the spinothalamic tract project to the periaqueductal gray and thus may be important link between ascending and descending pathways true or false

true