The Pathophysiology of Nociception and Pain.txt

• Peripheral receptors for pain are naked nerve endings of the primary neuron
• Nociceptors contain specialized ion channels that are activated by noxious stimuli
• 3 categories:
• mechanical: excess deformation
• thermal: temperature >45 or <5 activate TRPV1, TRPV2 channels; some also activated by capsaicin
• Polymodal: noxious mechanical, thermal stimuli, and chemicals; also activated by capsaicin

• action potential frequency: for stimulus intensity
• and duration of activity: for period of stimulation on the body

of nociceptors as well as second order and 3rd order neurons are larger: more convergence!

Noxious mechanical, thermal, and chemical stimuli activate specific ion channels on nociceptor terminals in the skin

• Some molecules: K+, ATP, H+ are released from damaged cells into the extracellular environment
• some molecules such as serotonin, histamine, NGF are secreted by cells upon stimulation
• Some molecules such as bradykinin and prostaglandin's (PGE2, PGD2) are enzymatic byproducts or receptor-stimulated products

• 1) they depolarize nociceptor terminals by directly activating ion channels/receptors: histamine serotonin, bradykinin, ATP, H+, K+
• 2) they lower the threshold for nociceptor action potentials by phosphorylating ion channels in the terminal (serotonin, bradykinin, prostaglandin, NGF)

• by enzymatic cleavage of HMW kininogen in plasma
• Prostaglandin synthesis: is initiated by the binding of molecules such as bradykinin to membrane receptors
• This activates phospholipases that cleave phospholipids to produce arachidonic acid, which is enzymatically modified to prostaglandins in mast cells
• and important enzyme in this sequence is CYCLOOXYGENASE

• Dendrites can release molecules in addition to receiving signals
• Electrical activity in one branch of a peripheral nociceptor terminal evokes simultaneous release of molecules from that branch as well as other branches as the depolarization spreads electronically

• sensory/receptive and secretory
• AXON REFLEX
• mediated by C fiber nociceptors
• Substance P and CGRP are neuropeptides, but here they act on non-neural cells: they are potent vasodilators

• 1) vasodilation
• 2) increased vascular permeability
• 3) increased pain - due to increased nociceptor excitability

• Histamine, serotonin, bradykinin, prostaglandin, substance P and CGRP: cause vasodilation and increased vascular permeability
• Substance P, serotonin: cause histamine release from mast cells

• vasodilation, increased vascular permeability and pain: part of healing process
• GOAL: to increase blood flow and prevent further damage by making the area painful to ensure protection

• Allodynia: generation of pain by stimuli that previously were not painful (touching sunburnt skin)
• Hyperalgesia: perceiving an increased sensitivity to pain - noxious stimuli evoke significantly more intense pain than normal
• Sensitization - has both peripheral and central causes

• changes at nociceptor terminals in the skin, which become more sensitive as a result of the inflammatory response
• the molecules released into the injured area: can
• 1) cause depolarization by binding to receptors on nociceptor terminals (histamine, bradykinin, ATP, H+)
• 2) cause receptor-mediated changes in nociceptor channel phosphorylation that facilitate channel activity (serotonin, bradykinin, prostaglandin, NGF)
• **These changes make nociceptors more sensitive and responsive by decreasing the threshold for evoking action potentials, increasing the frequency of action potential activity in response to noxious stimuli, or inducing spontaneous activity in nociceptors! which are normally quiescent
• ***can be reduced by application of COX inhibitors, which reduce prostaglandin synthesis and thus their effects on blood vessels and channel phosphorylation

Stimuli that were normally subthreshold in the spinal cord/CNS will evoke activity

• increased excitability of Second-order neurons and interneurons in the dorsal horn
• Physiological causes: enhanced efficacy of postsynaptic potentials in dorsal horn neurons
• decreased threshold for evoking action potentials in dorsal horn neurons

• an increased depolarization that activates NMDA receptors on spinothalamic neurons to cause Ca2+ influx.
• The increased Ca2+ can activate numerous molecules including phospholipas A2, which can lead to prostaglandin synthesis with subsequent effects on channel activity

• 1. Molecules bind to their receptors causing depolarization
• 2. Molecules bind to other receptors and modulate their activity
• 3/4. bradykinin, prostaglandin, histamine binding causes phosphorylation of channels and receptors
• 5. secreted molecules bind to receptors, become internalized, are transported to nucleus where they affect gene expression

• Windup: an acute condition in which repeated nociceptor activation causes a progressive increase in action potential frequency of spinothalamic neurons --> perceived as more intense
• Allodynia: light touch to an inflamed area causes pain; Due to some convergence in pathways, tactile mechanoreceptor axons make synaptic concoctions with spinothalamic neurons in the dorsal horn. Normally, these connections are not sufficient to evoke action potentials in the spinothalamic neurons. After Central Sensitization though, tactile stimuli can evoke action potentials in the pain fibers

usually declines as tissue heals, but with nerve injury sensitization is often sustained, resulting in neuropathic pain

is due to central sensitization, a prolonged increase in excitability of central neurons. it cannot be reduced by decreasing activity in first order nociceptors

the DRG cell bodies where they cause long-term changes in gene expression that alter levels of neuropeptides, ion channels, and receptors: results in long-lasting pain syndromes

the single most common reason for patient readmission following outpatient surgery

• the regions that modulate pain are in three locations:
• 1) midbrain: periaquiductal grey
• 2) dorsal lateral pons: locus ceruleus
• 3) medulla: raphia and other nuclei of the reticular formation

• these brainstem regions send axons to the spinal cord where they modulate the transmission of nociceptive signals from first and second order nociceptive neurons
• two important neurotransmitters used by the descending brainstem axons: serotonin from raphia nuclei in the medulla and NOREPINEPHRINE from locus ceruleus neurons in pons
• These transmitters excite opiate interneurons in the spinal cord to inhibit nociceptive signals
• Opiate interneurons: 1) presynaptically inhibit NT release from first order nociceptors and to 2) postsynaptically inhibit spinothalamic neurons

• modulate pain
• the PAG is activated by the hypothalamus and cortex in response to stressful and emotional situations
• Descending brainstem axons have both inhibitory and excitatory effects on nociceptive signals
• These different possibilities make it very difficult to understand and develop pharmacological strategies to treat pain

• reduce pain by stopping the transmission of nociceptive signals in the spinal cord through
• Electrical Stimulation
• Pharmacological treatments
• Surgical Treatment
• Placebo Effect

• stimulation of descending brainstem axons arising in the PAG causes a long-lasting reduction in pain
• first order tactile axons make inhibitory connections onto spinothalamic neurons: stimulation of the dorsal column axons sends action potentials back into the dorsal horn to inhibit nociceptors

• a patch containing electrodes is placed on the skin over a peripheral nerve associated with an injured area
• the stimulus is adjusted to excite large diameter (tactile) first order axons, which will inhibit nociceptive transmission in the spinal cord

• Opiates
• NE
• Antidepressants

have long-lasting inhibitory effects on pain transmission

• descending NA axons arise from pontine locus ceruleus
• these axons inhibit first order nociceptive terminals in spinal cord via alpha2-ARs and excite inhibitory interneurons via alpha1-ARs
• thus alpha2 and alpha1 agonists both can reduce pain

5-HT reuptake inhibitors potentiate the effects of serotonin, a pain modulator in the spinal cord

increase GABA activity

• glutamate is a transmitter for first order pain fibers
• excessive stimulation activates NMDA receptors, leading to central sensitization
• However, NMDAR antagonists cannot be used because they would cause severe cognitive deficits!

• capsaisin: binds to first order peripheral terminals of heat and polymodal nociceptors
• continued presence of it can desensitize these receptors to prevent their activation by inflammatory molecules in the injured area

• Tacotomy or Chordotomy: the lateral location of the ALS in the spinal cord makes it possible to sever these axons without damaging deeper areas
• this results in immediate cessation of pain
• However, this is transient and pain often returns after several months probably for several reasons involving sensitization at higher levels induced by the injury

the psychological expectation of an effect is enough stimulus to activate pain modulatory pathways