ALL ABOUT PAIN

The nervous system’s response to noxious (harmful) stimuli, also known as “nociception”

Examples of external stimuli: pricking, cutting, crushing, burning, freezing

Examples of internal stimuli: swelling, inflammation, distention (Note: These are noxious stimuli, but other stimuli must cause these stimuli—swelling, for instance, does not usually happen on its own)

Several factors contribute to reception of pain

Mechanical stimulation from sharp object

Potassium released from the insides of the damaged cells

Prostaglandins, histamines, and bradykinin from immune cells that invade area of inflammation

Substance P from nearby nerve fibers

So, What is Pain, Anyway?

There are Two “Waves” of Pain Nociceptors

Free nerve endings (dendrites) in the skin that pick up the information from the painful stimuli

Only responds to extreme pressure or temperature

Found almost everywhere: from skin to teeth pulp to joint membranes to muscles

Nociceptors are the dendrites of nerve fibers

There are two types of axons of these nerve fibers

A-delta fibers

C-nerve fibers (two types)

Both travel relatively slowly compared to other peripheral axons

A-DELTA NERVE FIBERS

First wave of pain (initial pain—sharp and highly localized)

Thick(er) and myelinated (moderately fast transmission)

Limited to responses from very strong pressure and extreme temperatures (tend to be from immediate stimuli)

C-NERVE FIBERS

Also known as “Polymodal nociceptors”

Second wave of pain (longer-lasting, duller, widespread pain)

Very thin and unmyelinated (very slow transmission)

Not limited to immediate stimuli—also respond to chemicals released by cells already damaged by burns, wounds, and infections ( this accounts for their long-lasting effect)

Just a little touch/pain humor….

….and something else to ponder.

Notice that the nociceptors labeled here are located in the EPIDERMIS and that they are FREE NERVE ENDINGS, or afferent nerve dendrites that are not encapsulated (as touch, heat, and pressure nerve endings are)

Cutaneous (“In the Skin”) Receptors

Pain’s Ascending Pathway to the Brain A-delta fibers and C-nerve fibers form synapses with dorsal horn of spinal cord

Cell bodies in dorsal root ganglia

Synapse between primary pain-sensing neurons and secondary pain-transmission neurons occurs in dorsal horn of spinal cord

Secondary neurons send signals upward through spinothalamic tract

Contralateral side of spinal cord

Face sends info through “mini-spinal cord” called trigeminal nerve into the medulla

Proposed by Ronald Melzack and Patrick Wall

Grew out of observations of WWII veterans and their injuries

Concept: pain messages are intercepted by specialized nerve cells in the spinal cord before they reach brainFor severe pain that could lead to damage

Nerve “gate” is wide openMessage travels almost instantaneously

For mild, weak painNerve gate sometimes closed Filter, block pain messages

Gate Control Theory

Nerve fibers that transmit touch influences gatekeeper cellsTouch stimulate gatekeeper cells to close

“gate”Decrease pain transmission

Rubbing sore area = relief

Gate Control Theory Cont’d

Pain and normal somatosensory neurons both synapse on projection cells (which go up into brain) and inhibitory interneurons in spinal cord

Normal somatosensory signals turns on both projection and inhibitory neurons= cancel each other out

Only pain turns on projection and inactivates the inhibitory- leading to pain

Gate Control Theory: In-Depth

Transmission:-Damaged Tissue-Thalamus-Parietal lobe and Limbic System-Cerebral Cortex

Pain and the Brain

When humans’ brains are mapped for response to lasers, this area activates.

While controversial, one area, the Vmpo, causes pain or temperature-related sensations when stimulated.

It gets messages from lamina I through the thalamus.

Lesions in the parieto-insular cortex reduces pain.

The Parieto-Insular Cortex

Medial Frontal Cortex

This is part of an area involved in controlling motivational behavior

It activates in response to perceiving the unpleasantness of pain

The parieto-insular cortex is responsible for the physical sensation processing

The anterior cingulate is responsible for the emotional response to pain

This theory suggests that pain in primates is “phylogenetically novel” because involved areas are large in primates, but especially large in humans

It could explain the effects of pain and the autonomic system on feelings

Simpler animals experience pain in the brainstem, but do not experience it cortically

One Possible Theory

The Descending Pathway

Descending system suppresses the transmission of pain signals from the dorsal horn of spinal cord to higher brain centers

Originate in the somatosensory cortex and hypothalamus

Thalamic neurons suppress ascending nerve signals at synapses in midbrain

Periaqueductal Gray

Also stimulate release of natural chemicals in body….

The Neurotransmitters of PAIN Nerves transmitting pain signals, as well as those involved in pain regulation, use excitatory and inhibitory neurotransmitters

Excitatory Neurotransmitters of Pain Signaling Glutamate—

-NMDA , AMPA, and metabotropic receptors are involved in excitatory synaptic transmission of pain.

-With NMDA (C-fibers), Mg++ clogs receptor

-Nearby peptide receptors stimulatedchannel opens

-Depolarizes the neuron

Tachykinins—-G-protein coupled receptors-Neurokinin A binds to NK-2 receptors, and

Neurokinin B binds to NK-3 receptors

Substance P (The “P is for Pain” Molecule), a Tachykinin

-Found in C-fibers-First described by von Euler & Gaddum in

1931 during research of equine brain and intestines

-Sequenced in 1971-Binds to NK-1 receptors , but is synthesized

by nociceptors-Vasodilation (swelling of capillaries) and

release of histamine by mast cells (see below)

Neurotensin-Detected during isolation of Substance P

from bovine samples-Causes vasodilation in already-open wounds

Histamine-In mast cells of the immune system; subtance P and foreign substances like bee venom cause release onto nociceptors, triggering depolarization-Also “punctures” blood capillaries, causing swelling and redness at location of injury

ATP-Released by damaged cells and binds to ATP-

gated channels on nociceptors (then the cell is depolarized...)

-Neurotransmitter associated with prostaglandin (a hormone)

H+—from build up of lactic acid, activate H+-gated channels

Potassium Ions-Released by damaged cells; indirect

depolarization of nociceptors

Proteases-Break down kininogen from outside cell into

bradykinin, which binds to receptors opening ion-gated channels

Calcitonin and other neuropeptides (there are MANY that are related)

NOTE: THESE ONLY APPLY TO CERTAIN A-DELTA AND C-FIBERS

-There are certain c-fibers known as IB4-positive fibers, which so far only seem to bind to plant isolectin

Inhibitory Neurotransmitters of Pain Signaling Most important: GABA

-Ligand-gated and G-protein coupled receptors-Most important for interneurons (gate-control theory)

Glycine

Neurotransmitters Mediating Pain Regulation-Serotonin and Norepinephrine are involved in transmission between neurons of the descending pathway

-Often working in tandem with Substance P

A Remarkable Discovery with FosShows up in the spinal cord after even brief noxious stimulation, particularly of C-nerve fibers, but disappears after 2-7 days; expression of C-Fos gene in damaged nerves that do not typically express Fos

An Inducible Transcription Factor, which changes the internal environment of the cell on a long-term basis

Therefore, provides a link between persistent stimulation and consequences for the future by gene expression!

Although the transcription of C-Fos is understood generally, itsprecise mechanisms involvingneurons, especially concerning cellReplication, are not quite understood

How the Pain We Feel is Different

Different types of nerves and neurotransmitters

Nociceptors are simultaneously activated with other cutaneous receptors, like mechanoreceptors, giving us:

-Pressure-pain-Hot-pain

-Cold-pain-Etc.

As for spicy foods….

Spicy Foods are Moderated by Capsaicin

First isolated as a vanilloid in red peppers (then chilies, jalapeños….)

Simultaneous activation of nociceptors by capsaicin and taste receptors by other ingredients provides for different “types” of spicy

Selective activation of C-fibers (and sometimes A-delta fibers)

Depolarization of unique ion-gated channel with “vanilloid” receptor -VR1, vanilloid receptor subtype 1

has a very specific antagonist, capsazepine

“Excitotoxin”-death of neurons of the dorsal root ganglion with prolonged exposure

BUT just the right amount of repeated application results in depletion of substance P

Pain that lasts 6 months or longerPersists long after trauma has healed or

in the absence of traumaCommon causes of chronic pain

Physical problems stemming from chronic illness or internal injuriesArthritis: inflammation of the joints

Damage to peripheral or spinal nervesNeuropathic painCan result from accidents, infections, surgeryUnknown cause (possibly psychological?)

Chronic Pain

Autoimmune DiseasesMS, lupus

CancerCompression/

TraumaCrush nerves

DiabetesMost common

Drug side effects

Nutritional Deficiencies

Infectious DiseaseLyme disease,

herpes, HIVToxic Substances

Mercury, lead, arsenic

More Causes of Pain and Nerve Damage

“Off” Perception of Pain Allodynia—“painful” response to a typically non-painful stimulus Hyperalgesia—increased “painful” response to a painful stimulus

Pain Enhancement during illness Stops person from wasting energy Immune system interaction?

Pain Enhancement after Injury Damage to/recent activation of nocioceptorsrespond to weaker stimuli (use of local anesthetics) Stops person from touching wounds/getting infections

Sensitization

Nervous system amplifies and distorts painResulting pain out of proportion to original injury

or diseaseCauses

Inflammation: nociceptors fire w/ greater intensity, longer time, lower threshold

Abnormal chemical reactions in spinal cord that increase transmission of pain messages

Lower threshold of pain receptors Examples of Sensitizers: bradykinin,

prostaglandins, and substance PLinked to sensing, feeling, and thinking

regions of brainLeading to emotional, psychological suffering

But Don’t Forget the Most Curious Substance of All.....~Endorphins, or Endogenous Morphine-like

Substances

In the late 60s, researchers identified the so-called opioid receptors: mu, kappa, and delta

Increasing identification of opioid antagonists (ex. Naloxone)

We must have a natural substance in our brain such that we would from an evolutionary perspective require, or at least benefit from, the presence of opioid receptors

In and around 1975, discovery of the Met-enkephalins (Methionine), Leu-enkephalins (Leucine), dynphins, and Beta-endorphin, which bind to opioid receptors

-Proenkephalins are produced by the cell body then split into active peptides

-Enkephalins then hyperpolarize the neuron by inhibiting excitatory neurotransmitters

PAIN CONTROL

Which Leads Us To……

Ascending Regulation Simultaneous activity in A-beta fibers (low-threshold mechanoreceptors) ex. Massaging bruises

Descending Regulation Electrode Therapy Perhaps most important: electrical stimulation of the PAG

Input from the thalamus and other structures Medulla, especially raphe nuclei, using serotonin back to dorsal horn of spinal cord

Drug-Mediated Management Partial and full opioid agonists

ex. Morphine, heroine, fentanyl, oxycodone, demerol Nerve terminals of primary pain neurons in dorsal horn contain opioid receptors, activation of which inhibits transmitter releaseInjection of opioids into midbrain can cause profound pain relief (connected to primary pain neurons)

CCK Antagonists Mu receptor activation releases CCK, which goes on to inhibit opioid effects (through activation of other substances, such as substance P)

Corticosteroids (anti-inflammatory medications) Capsaicin (sounds counterintuitive, I know….)Anesthetics (nitrous oxide, PCP, cocaine) Cannabis

NSAIDs Inhibit prostaglandin Tend to inhibit all prostaglandin—analgesia and anti-inflammation, but no muscle regeneration

Anti-Histamines Reduce swelling and irritation at injury site

Antidepressants

Stress-Induced Analgesia Endorphins

Suppress glutamate and hyperpolarize neurons In response to stress and physical exertion

Belief-Induced Analgesia “Placebo Effect”

Other Therapies

Surgery (an extreme) Psychedelics and caffeine for headache relief Alternative Therapies: hot/cold compresses, chiropracty, massage, hypnosis, herbal medicines, acupuncture

Pain Tolerance Pain tolerance is generally higher in men than in women, and decreases with age

In men pain tolerance increases significantly in repeat testing

Researchers expect that gender role expectations effect how men perform on the test

A woman’s ability to handle pain may also relate to where she is in her hormone cycles

In animal studies it was found that females have fewer opioid receptors than males, which may account for gender differences.

More connections

to regions of the brain

associated with external

functions

More connections

to regions of the brain

associated with internal

functions

And Now, Some Weird Stuff……

Music and Pain

An hour a day keeps the doctor away

Phantom limb pain—pain without stimuli or receptors

Ramachandran Destruction of nerves and pain modulation Mirror therapies

SCN9A, CIPA and EvolutionSCN9A instructs the protein sodium channel that allows neurons to pass on messages

In a study of children where this was faulty, scientists found that they felt no pain

They frequently bit their lips and two of them had bitten at least a third of their tongue off. In fact, one girl thought it was funny to bite her fingers and see the blood.

In a study of people who had too much of SCN9A, the people experienced chronic burning in their extremities

CIPA is a nerve disorder in which the nerves for sensing temperature and pain don’t form

Mutations of the NTRK1 gene—NGF binding to TrkA receptor on nociceptive and sympathetic nerves not encoded

Some estimate that CIPA affects approximately one in 125,000,000

Issues: Common infections -> amputation

Accidentally biting tongue through or clean off when eating Dying of overheating

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