• sun burn, burning mouth syndrome, trigeminal neuralgia, TMD

• an increased amount of pain associated with mild noxious stimulus
• involves both 
  • peripheral sensitization: nociceptive nerve terminals
  • Central sensitization: facilitation of transmission at level of dorsal horn and thalamus

nociceptive receptors sensitized by products of COX enzymes (PGE2)

• nociceptive responses to bradykinins, 5HT, histamine, adenosine, ATP and PGs were enhanced

• at level of dorsal horn and thalamus
  • dental: trigeminal ganglia
• complex facilitation at both supraspinal and spinal levels
• dorsal horn neurons to nociceptive inputs display the phenomenon of wind-up
  • synaptic potentials steadily ↑ in amp. with each repeated stumulus

• myelinated Aδ fibers and unmylinated fibers
  • cell bodies within DRG
  • fibers synapse with nociresponsive neurons
• n.t at junction between 1º afferent terminals and spinal cord nociresponsive neurons are:
  • excitatory aa's: glutamate
  • neurokinins: substance P, neurokinin A

• have NMDA receptors at synapse
• when bound by substance p (SP) or glutamate:
  • causes pain
  • stimulates NOS system which causes release of NO, which re-stimulates release of SP and glutamate (+feedback)

• activates AMPA & NMDA receptors
  • activation of AMPA receptors causes a rapid memb depolarization
  • activation of NMDA receptors causes a slow developing 2º depolarization
  • NMDA activation, resulting in Ca influx, which activates the Ca-calmodulin-dependent nitric oxide synthases (NOS) to yield nitric oxide (NO)

• can cause retrograde stimulation of 1º afferent nerve, increasing further release of glutamate
• thus even small release of glutamate eventually leads to larger amounts of glutamate release - wind up

• a good pharm target to treat pain
• ex: L-NAME (L-N-nitro-arginine methyl ester) inhibits NMDA therefore NOS

NMDA receptors

(N-methyl-D-aspartate)

• subset of glutamate receptors
• normally associated with Mg ions in the inactive state
• when activated, Mg dissociated from receptor, allowing it to be activated by agonist
• role in chronic pain, phantom limb, and tooth pain
• inhibited by Ketamine, dextromethrophan (DM) 

• Ketamine (parenteral anesthetic)
• dextromethrophan (DM) (morphine like)

Substance P antagonists

• also called Tachykinin antagonists
• modifications of amino acid sequence of substance P
• ex: Spantide

• activates neurons conducting thermal pain
• causes release and depletion of substance P form afferent a neurons and spinal interneruons

• Developed by WHO

1. simple analgesics: acetaminophen, NSAIDs
2. opioid suitable for moderate pain ± simple analgesics
3. opioid suitable for severe pain ± simple analgesics
4. adjuvant analgesics may be required at any step

• Heterogeneous group of drugs
• enhance effects of conventional analgesic
• examples:
  • tricyclic antidepressants
  • anti-epileptics
  • caffeine

• tricyclic more effective than SSRI
• TCA: amitriptyline, doxepin, desipramine
  • effective in postherpetic neuralgia, diabetic neuropathy, migraine, and neuropathic pain syndromes
  • ↑ monoamines release from descending pain pathway
    

• cabamazepine, gabapentin, phenytoin and valproate
• effective in trigeminal neuralgia, posterpetic neuralgia and burning mouth
• inhibits transmission of pain impulses to supraspinal sites
• used for low to moderate pain

1. Tricyclic antidepressants
2. Local anesthetics, ketamine, clonazepam
3. Anti-epileptic :

•  
  • carbamazepine
  • phenytoin
  • gabapentin
  • baclofen

• locally modulate pain
• aim to minimize adverse effects (↑ local [ ]s lower plasma [ ]s)
• Clinical use: cutaneous pain, muscle pain, joint pain, musculoskeletal and soft tissue injuries, RA, OS, solar keratoses
• formulations: cream, ointment, gel, spray, patch
• examples: diclofenac