Pain sensations

Dr Raghuveer Choudhary

Damaged tissues release proteolytic enzymes, K+ &histamine .Proteolytic enzymes act on globulins in the interstitial Fluid to release kinins. e.g bradykinin, K+ and histamine stimulate pain receptors Pain is a protective sensation.

Pain receptors . Free nerve endings Three types 1. Mechanical pain Receptors.: stimulated by mechanical injurious stimuli. 2. Thermal pain Receptors. : discussed before. 3. Chemical pain Receptors.: stimulated by chemical stimuli. Chemical stimuli include: bradykinin (most important) serotonin, histamine & K+.

Distribution of pain receptors - More : Skin, periosteum, arteries, joint surfaces, & tentorium cerebelli and cranial sinuses. - Less : deep tissues. - Absent : liver parenchyma, lung alveoli and brain. Nerve fibres: A delta and C fibres. Adaptation: Slowly (static-tonic) or nonadaptive receptors.

Types of pain
Pain is classified according to the: (a) Site of pain 1. Cutaneous pain. 2. Deep pain. 3. Visceral pain. (b) Quality of pain 1. Epicritic i.e sharp pricking pain. 2. Protopathic i.e dull aching pain. 3. Burning pain.

(1) Cutaneous Pain
‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡

Fast (Immediate, acute sharp or pricking) Felts within 0.1 sec ond . Short-duration. Mechanical &ThermalR. A delta fibres. Ends in cerebral cortex. Well localized. Not felt in deep tissues Blocked by hypoxia & pressure Neospinothalamic tract Neurotransmitter: Glutamate .

‡ Slow (Chronic, burning, aching throbbing nauseous) After one second . Prolonged;annoying,intolerable. Elicited by All types of R. C fibres Ends in non specific thalamic nuclei & Reticular formation. Poorly localized . Occurs in skin & deep tissues Blocked by cocaine. Paleospinthalamic tract Neurotransmitter Substance P.

Nociceptive Pathways
‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Fast A Delta Fibers Glutamate Neospinothalamic Mechanical, Thermal Good Localization Sharp, Pricking Terminate in VB Complex of Thalamus ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Slow C Fibers Substance P Paleospinothalamic Polymodal/Chemical Poor Localization Dull, Burning, Aching Terminate; RF
± Tectal Area of Mesen. ± Periaqueductal Gray

Nociceptive Pathways
‡ Spinothalamic - Major
± Neo- Fast (A Delta) ± Paleo- Slow (C Fibers)

‡ ‡ ‡ ‡

Spinoreticular Spinomesencephalic Spinocervical (Mostly Tactile) Dorsal Columns (Mostly Tactile)

PAIN
‡ A-DELTA Noxious Stimulation change in Membrane Potential Receptor Potential A. P. ‡ C-FIBERS: Damaged Cell Proteolytic Enzymes

Circulating Gamma Globulins Bradykinin, Substance P Stimulation of Nerve Ending

Fast pain is transmitted by A delta fibers (5-15 m/sec.) from skin (mainly), parietal pleura, peritoneum a & Synovial membrane.

(1) Somatic (motor) reflexes:- Spinal reflexes. Flexor withdrawal reflex. (2) Autonomic reactions:Cutaneous pain: Pressor effects (increased heart rate & ABP). DEEP & visceral pain: Depressor effects (decreased heart rate & ABP). (3) Emotional reactions:-Acute pain: Crying and anxiety. (4) Hyperalgesia:- mainly due to skin lesion. (increased pain sensibility).

Appreciation of pain - Fast pain; is appreciated in thalamus and cortex. - Slow pain; is appreciated mainly in thalamus.

Functions of the cortex in pain appreciation 1. Localization of pain 2. Discrimination of type of pain. 3. Modulation of pain by emotional and behavioral factors.

Arousal reaction to pain signals
The non specific thalamic nuclei (intra-laminar nuclei) and reticular formation have a strong arousal effect on the brain which prevents sleep during pain.

Deep pain C. Fibres
Diffuse, Dull aching and Depressor effects. Causes: - inflammation, ischaemia or muscle spasm. - Bone fractures; due to stimulation of periosteal pain receptors. Characters of deep pain 1. Dull aching or rhythmic cramps. 2. Diffuse (poorly localized). Depressor autonomic changes: decreased heart rate, decreased arterial blood pressure ,nausea & vomiting.

DEEP PAIN
‡ Arises from Periosteum & Ligaments ‡ Continuous Contraction of Muscles ‡ Poorly Localized ‡ Associated with Sweating & Changes in Blood Pressure ‡ Often Nauseating ‡ Transmitted via Antero Lateral System

Ischaemic pain
Type of deep pain felt in muscles when their blood supply is decreased. The Patients complains of severe pain in the muscles upon walking or running due to accumulation of pain producing substances as lactic acid. Examples 1. Cardiac muscle: angina pectoris. 2. Skeletal muscle: intermittent claudication.

Visceral pain C Fibres
Most of viscera contain only pain receptors. Pain from viscera is carried a long; C fibres. Pain from peritoneum, pleura or pericardium:Adelta. It differs from cutaneous pain . Sharp cut in the viscera does not cause pain (why). . Diffuse stimulation of pain nerve ending ® severe pain.

Causes Of Visceral Pain 1. Ischaemia: increased acidic metabolites, bradykinin & proteolytic enzymes. 2. Inflammation of peritoneal covering of viscera. 3. Irritation (chemical irritation by HCI in peptic ulcer). 4. Overdistension of a hollow viscus e.g urinary bladder. 5. Spasm of a hollow viscus e.g gut, gall bladder or ureter. Both 4 & 5: Obliteration of blood vesssels ® Ischaemic pain.

Characters of visceral pain 1. Dull aching or rhythmic cramps. 2. Diffuse (poorly localized). 3. Depressor autonomic changes: decreased heart rate, decreased arterial blood pressure ,nausea & vomiting. 4. Rigidity of the overlying muscles. Limitation of the spread of infection. Decrease the mobility of the diseased viscus for relief of pain. 5. Referred to the surface area i.e referred pain.

VISCERAL PAIN
‡ Arises from Visceral Organs ‡ Receptors
± Free Nerve Endings of A Delta & C Fibers ± Sparsely Distributed

‡ Stimulus: Spasm, Distension, Ischemia, Chemical ‡ Ischemia
± Release Acid Metabolites ± Tissue Degeneration Products Produce Bradykinin & Proteolytic Enzymes

‡ Chemicals
± Release of Proteolytic Acid Gastric Juice

VISCERAL PAIN
‡ Input to CNS via Autonomic Nerves ‡ Cell Bodies of Ist Order Neuron
± DRG & Homologous Cranial Nerve Ganglia of VII, IX , X & Trigeminal Nerve

‡ Afferent also Enters via Sympathetic Ganglia for Reflex Control of Visceral Functions

VISCERAL PAIN
‡ In CNS Fibers Follow Same Route as that of Other Pain Fibers
± Poorly Localized, Unpleasant ± Associated with Autonomic Changes & Nausea ± Usually Referred to Superficial Parts of Body

‡ REFERRED PAIN
± Visceral Pain Usually Referred ± Deep Pain May Also be Referred

Referred pain
Definition Pain originating from viscera but felt in somatic structures which supplied by the same spinal dorsal root ( the same dermatome) of the diseased viscus.

Referred pain
Examples 1. Cardiac pain: is felt in left shoulder. 2. Gall bladder pain: is felt in tip of right shoulder. 3. Appendicular pain: is felt around the umbilicus. 4. Gastric pain: is felt between the umbilicus & xiphoid process. ‡ 5. Renal pain: is felt in the back, inguinal region & testicles. ‡ 6. Teeth pain: referred to other teeth. ‡ ‡ ‡ ‡ ‡

REFERRED PAIN
‡ Superficial Pain Never Referred ‡ Visceral Pain - Local & Referred
± May also Radiate to Distant Site ± Cardiac Pain
‡ Inner Aspect of Left Arm, Right Arm, even to Neck & Abdomen

± Distension of Ureter
‡ Pain in Testicles

± Irritation of Parietal Plura & Peritoneum
‡ Pain Referred to Overlying Surface of Body

± Of Diaphragm
‡ Tip of Shoulder

REFERRED PAIN
‡ Mechanism
± Dermatome Rule
‡ Parts Develop from Same Embryonic Segment or Dermatome ‡ Diaphragm Migrate from Neck ‡ Heart & Arm have Same Segmental Origin

‡ Convergence
± Somatic and Visceral Pain Afferents Converge on Same Second Order Neuron ± Brain Unable to Differentiate Site of Origin
‡ Hence Pain Felt at Somatic Sites

Mechanism of referred pain
a. Convergence projection theory Afferent pain fibres from the skin and viscous converge on the same cells of SGR or thalamus and will finally activate the same cortical neurons. Whatever the source of pain, the cortex will project it to the skin being the commenst source of pain.

b. Facilitation theory

Afferents of diseased viscera, give facilitation to cutaneous pain cells in Substantia Gelatinosa of Rolandi (SGR), Which leads to facilitation of their stimulation.

REFERRED PAIN
‡ Facilitation Effect:
± Activity in Visceral Pain Afferents Collaterals Fibers EPSP in Spinal Neurons Receiving Somatic Inputs Activity in Somatic Neurons Continuous Pain

PAIN
‡ Intensity of Pain is Proportional to Degree of Tissue Damage ‡ Ischemic Pain Lactic Acid Nerve Ending Stimulation ‡ Muscle Spasm Mechanoreceptor Stimulation Ischemia ‡ Transmission of Pain
± A ± Delta Fibers: 6 to 30 M/Sec ± C ± Fibers: 0.5 to 2 M/Sec

PAIN
‡ Mixed Spinal Nerve ‡ Dorsal Root Ganglia Horn ‡ A ± Delta Fibers Dorsal Root Dorsal

± Terminate in Lamina I of Dorsal Horn Gray Matter (Fast Pain)Give Local Collateral Branch for Spinal Reflexes

‡ Second Order Neuron
± Cross to Opposite Side ± Form Anterior Spino-Thalamic Tract (Neospinothalamic Tract)

‡ Joins Medial Laminiscus

Few Collaterals to R.F.

PAIN
‡ Second Order Neuron Thalamus Post Central Gyrus ‡ ‡ ‡ ‡ Localization is Good Neurotransmitter is Glutamate Few Fibers Ascends in Dorsal Column Slow pain: C ±Fibers Ist Order Neuron Lamina II and III

PAIN
‡ Substantia Gelatinosa of Rolando ‡ Interneuron Lamina V Second Order Neuron Cross Lateral Spinothalamic Tract ‡ (Paliospinothalamic Tract Brain Stem Joins Medial Leminiscus Thalamus Cortex

Pain
‡ Brain Stem: Collaterals Given to:
± Reticular Formation at All Levels of Brain Stem ± Hypothalamus ± Peri Ventricular Gray Matter ± Peri Aqueduct Gray Matter ± Most Fibers End in Intralaminar and Reticular Nuclei of Thalamus ± Non Specific Thalamo Cortical Projections to All Part of Cerebral Cortex ± To Somato Sensory Cortex SI and SII

PAIN
‡ While Entering Spinal Cord
± Fibers Ascends or Descends Few Segments Spinal Cord Enters

‡ Through Many Inter-Neurons
± Information Relayed to Anterior Horn Cells of Same & Opposite Side for Local & Segmental Reflexes of Spinal Cord

‡ Pain & Other Crude Sensations
± Perceived Even in Absence of Cerebral Cortex

PAIN

‡ Cortex is Concerned With
± Discriminative, Exact & Meaningful Interpretation of Pain ± Emotional Components of Pain

‡ Post Injury Pain
± Irritation of Nerve Endings

‡ Allodynia
± Minor Touch Causes Pain

‡ Neuropathic Pain
± Occur at Sites Even after Healing of Injury ± Often Resistant to Analgesics

PAIN
‡ Mechanism
± Release of Sensitizing Substance ± Transmission at Synaptic Junctions ± At Finer Level
‡ Activity of Pre-Synaptic NMDA Receptors of Primary Nerve Ending Release of Substance P

± Gene Switch
‡ Sub Population of A-Beta Fibers from Mechanoreceptors Inputs Start Producing Substance P ‡ NMDA(N-methyl-D-aspartate)
± Ion Channels Allow Entry of Ca++

Pain Control Mechanisms
‡ Peripheral ‡ Gating Theory
± Involves Inhibitory InterNeuron in Cord impacting Nociceptive Projection Neurons
‡ Inhibited by C Fibers ‡ Stimulated by A Alpha & Beta Fibers ‡ TENS

‡ Central ‡ Direct Electrical + to brain Analgesia ‡ Nociceptive control Pathways Descend to Cord ‡ Endogenous Opioids

Pain Modulation
‡ Examples
± Stress Analgesia ± War Situation When Person Emotionally Charged ± Pain Relieved by
‡ Acupressure & Acupuncture and Electrical Vibrator

‡ Gate Control Mechanism
± Proposed by Malzek & Wall

Pain Control Systems
(I) Analgesic system a) The neurons of the periaqueductal gray area are stimulated by B endorphin reaching them from hypothalamus (neurons of periventricular area) or pituitary (through blood). b) Fibres of periaqueductal and interneurones of sp.cd. Secrete (Enkephalin) c) Fibres of raphe magnus nucleus secrete (Serotonin) d) Inhibitory interneurones in spinal cord secrete (Enkephalin).

PAIN
‡ DESCENDING PAIN INHIBITING SYSTEM: ‡ Fibers Arise from: Peri-Aqueductal Gray matter Peri-Ventricular Gray Matter Hypothalamus Medial Forebrain Bundle Neurons around IIIrd & IV ventricle
Encephalins

Nucleus Reticularis in Medulla Spinal Cord Nucleus Raphe Magnus

PAIN
‡ Nucleus Raphe Magnus
Serotonergic Neurons

‡ Dorsal Horn of Spinal Cord in Substantia Gelatinosa ‡ Pre-Synaptic and Direct Inhibition by Blocking Ca ++ Channels ‡ Blocking of Pain Signals

(II) Brain Opiate System
Opiate receptors in the brain cause pre and postsynaptic inhibition of the nociceptive pathway.

Sites of opiate receptors 1. Periaqueductal gray area 2. Periventricular aea. 3. Raphe magnus nucleus in medulla. 4. Substantia nigra.

Opioid peptides
(1) Enkephalins. Act as neurotransmitters at the analgesic system. (2) Endorphins -In hypothalamus act as neurotransmitters. -In pituitary act as hormone. Release during stress leading to stress analgesia. (3) Dynorphin Very potent analgesic.
Types of opiate receptors Delta, Mu, Kappa, Sigma & Epislon.

BRAIN OPIOID SYSTEM
‡ Opium
± Alkaloid ± Morphine Derived from Opium ± Receptors are Opioid Receptors
‡ Found in Many Areas of Brain
± Limbic System Hypothalamus, Peri-Ventricular Areas, Pituitary & Spinal Cord

Analgesia

‡ Endogenous Substances which Mimic Action of Opium Opioid Peptides
± Brain¶s Own Morphine ± Act like Neurotransmitter on Opioid Receptors

BRAIN OPIOID SYSTEM
‡ Opioid Peptides
± Beta Endorphins
‡ Derived from Pro-opiomelanocortin

± Met-and Leu-Encephalins
‡ Derived from-Proencephalins

± Dynorphin ± Derived from Prodynorphin

‡ Opioid Peptides Cause Pre-synaptic Inhibition
± At Spinal Cord to Block Pain
‡ Inhibit Release of Substance P

BRAIN OPIOID SYSTEM
‡ Cause Post Synaptic Inhibition
± Produce IPSP

‡ In Limbic Areas & Hypothalamus
± Pain Modulation

‡ Act Peripherally at Site of Injury ‡ Opioid Mediated Endogenous Analgesia System Activated by Administration of Exogenous Morphine ‡ Descending Analgesia System
± Under Tonic Inhibitory Control of Mid Brain & Medulla ± Opiates Inhibit these Inhibitory Inter-Neurons

(III) Gate theory
1) Spinal gate: SGR (substantia gelatinosa of Rolandi) in layers II & III acts as gate. At this level, there is a group of inhibitory enkephalinergic interneurons which form the "Pain Inhibitory complex, PIC". When stimulated, these interneurons block the transmission of pain sensation by presynaptic inhibition of pain-conducting fibers.

This gate can be closed by: Impulses from 1. A beta fibres: (rubbing of skin inhibits pain). 2. A delta fibres; counter irritant and acupuncture inhibit pain. They stimulate cutaneous receptors which send impulses through A delta fibres stimulate the PIC. 3. Cortico-fugal fibres: (thinking decrease pain). All these fibers causes presynaptic inhibition of pain by activating an interneurone which secrete (GABA).

2)Thalamic gate:
The same "gating" mechanism for pain is found also at the thalamus where pain signals could be blocked by corticofugal fibers or facilitated by intralaminar thalamic nuclei. In this way, the thalamus considered as a secondary gate far pain transmission.

Stress analgesia; During stress, Pain is blocked at two levels :
A) At the thalamus: (the second gate of pain transmission ). Corticofugal fibers to the thalamus block by presynaptic inhibition the transmission of pain signals in the thalamus before they reach the cerebral cortex.

B) At the dorsal horn of the spinal cord: (the first gate of pain transmission).
The hypothalamus, and other parts of the central analgesia system, activate the spinal PIC which blocks the transmission of pain signals at the dorsal horn.

Melzack and Wall (1965, 1988) developed a comprehensive theory of pain ( gate-control theory ) which has generally received wide support Fast touch fibres and slow pain fibres connect with substantia gelatinosa (SG) and transmission cells (T cells) in spinal cord T cells send pain information to the brain SG acts as gate to allow or inhibit T cells

GATE CONTROL MECHANISM

Spino Thalamic Pathway

Type II Fibers (-) (-) (+) S.G.Cells (-) (-) A-DELTA & C Fibers

T- Cells (+)

Activity in fast fibers tends to close the gate (touch but no pain) and slow fibers open the gate (pain)
A light touch accompanying a noxious stimulus partially closes gate (reduces pain) rub skin to alleviate pain Psychological factors? Modify gate via descending pathway and/or release of endogenous opiates (e.g. endorphins) in the CNS producing analgesic effects. Ignore pain to escape from greater danger (e.g. death!)

Headache
‡ Brain is insensitive to pain. ‡ Pain sensitive intracranial structure; ‡ (Arteries, Veins, Nerves and Dura at the base of the brain) ‡ Headache is referred pain ‡ a. Supratenterial is referred along the ophthalmic n ® frontal Head ache. ‡ b. Infratentorial is referred along Cervical 2 ® occipital Headache.

Causes of intracranial headache: 5% 1. Meningeal irritation; me nin gitis ; gen eral ize d. Br ain tum our; loca lize d. 2. Migraine headache; Abn orma l va scul ar phe nom eno n. 3. Hypertension: He ada che a pu lse Pre ssur e. 4. Low CSF pressure: Rem oval of 20 ml of CS F. ® bra in desc ent ® tra ctio n of th e d ura & h ead ache . 5. Alcoholic headache al coh ol pr odu ces dir ect meni nge al irrita tio n. 6. Constipation. Ab sorp tion of tox ins pro duce s di rect me nin geal irri tati on.

Causes of intracranial headache: 5%
‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ 1. Meningeal irritation; meningitis ; generalized. Brain tumour; localized. 2. Migraine headache; Abnorma l vascular phenomenon. 3. Hypertension: Headache a pulse Pressure. 4. Low CSF pressure: Removal of 20 ml of CSF. ® brain descent ® traction of the dura & headache . 5. Alcoholic headache alcohol produces direct meningeal irritation. 6. Constipation. Absorption of toxins produces direct meningeal irri tation.

Causes of extra-cranial headache 95%
‡ 1. Muscular spasm of scalp and neck muscles due to emotions . ‡ 2. Irritation of the nasal sinuses. ‡ 3. Errors of refraction . ‡ 4. Otitis media. ‡ 5. Toothache.

Hyperalgia(increased pain sensation)
‡ 1. primary hyperalgesia; ‡ It occurs in the inflammed skin due to decreased threshold of pain receptors ‡ by bradykinin, K, Histamine and prostaglandins. ‡ So non painful stimuli become painful.

Hyperalgia
Secondary hyperalgesia; It occurs in normal skin due to increased threshold of pain receptors. So pain receptors need stronger stimulus, but once pain is elicited ,it is very severe It can be explained by (Convergence facilitation theory). Impulses from the injured area facilitate a central neuron. Impulses from the area of secondary hyperalgesia converge on same central neuron. The convergence on a central facilitated neuron explains the exaggerated pain sensibility.

Why the threshold of pain is increased in the area of secondary hyperalgesia. The facilitator neuron which arises from the area of primary hyperalgesia exerts lateral inhibition on the stimulator neuron which arises from the area of secondary hyperalgesia.

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