Nociception: Modulation Pain Outlines Topics Nociception: Transduction Nociception: Transmission Nociception: Modulation The ANS Pain measurement Epidemiology of mental illness Deafferentiation pain Peripheral neuropathies and neuralgias Sympathetic dystrophies Central pain syndromes Post-herpetic neuralgia Extremity pain Low back pain Headache Pediatric pain Antidepressants Anticonvulsants Neurolytic blocks Celiac plexus block Neurosurgical procedures Epidural steroids Local anesthetics Psychological techniques Spinal stimulation TENS

1. HYPOTHALAMUS                   Periventricular matter

   MIDBRAIN (opioid)
   	periaqueductal grey matter
   PONS(norepinephrine)
   	dorsolateral pontine tegmentum
   MEDULLA (serotonin)
   	rostroventral medulla
   SPINAL CORD
   	reticulospinal tract, dorsolateral funiculus
   LAMINAE I, II, V

   
   

2. Opioid agonists

   Opioids act directly on the CNS. Area of action include the periventricular grey, periaqueductal grey, rostroventral medully. Opioids act in part by activating descending antinociceptive pathways. Supraspinal opioids lead to increased spinal levels of NE and serotonis, and the effect of opioids can be decreased by spinal administration of NE and/or serotonin antagonists.

   Opioid modulation appears to originate in the periaqueductal grey matter (midbrain) and the periventricular grey matter lateral to the hypothalmus. The fibers project to the spinal cord via the reticulospinal and dorsolateral funiculus to laminae I, II, and V.

   
   

   1. u opioid agonists
      There is a slow increase in daily opioid requirements, usually doubling every few months
      1. Dose increases are slower for intrathecal versus epidural administration. Fibrosis around the epidural catheter can lead to pain on injection or tracking of the medication out of the epidural space.

      2. Dose increases are slower in patients receiving infusions versus intermittent bolus injections. This may be due to alterations in the development of tolerance.

      Opioids are most effective for somatic pain, followed by visceral pain, and is least effective for neurogenic pain.

      Incident pain is difficult to control

      High systemic doses of opioids predict high spinal doses of opioids.

      Chronic non cancer pain is more resistant to spinal opioids than cancer pain.

      More potent opioids may be more effective than less potent opioids secondary to the development of tolerance and the agonist/receptor interaction.

   2. d opioid agonists

   1. represented by DADL, enkephalin
      
   2. can provide analgesia
      
   3. associated with somnolence
      
   4. Tolerance does occur, but cross tolerance with u agonists may not occur

a-2 (norepinephrine)adrenergic agonists

1. Norepinephrine, via a2 receptor, inhibits the discharge of dorsal horn neurons and decreases the response of animals to noxious stimulation. Appears to originate from the lateral and dorsolateral tegmentum of the Pons. Neurons then project to the periaqueductal grey matter, rostroventral medulla to the spinal cord. NE is also involved in opioid mediated analgesia. Yohimbine, an a2 antagonist, will decrease analgesia produced by systemic opioids.

2. These are agents such as clonidine and ST-91
   
3. Appears to restore effectiveness of opioids
   
4. May be associated with less tolerance than opioids

GABA receptor agonists

1. Baclofen
   1. GABAB receptor agonist
      
   2. Leads to analgesia when administered intrathecially
      
   3. Tolerance does develop, but not to the extent seen with opioids.
      
   4. Can provide analgesia in opioid tolerant animals.
      
   5. Produces dose-dependent motor block in the lower extremities.

2. Benzodiazepines

1. GABAA receptor agonist: acts to augment the activity of GABA receptor stimulation.
   
2. Has been shown to produce analgesia when administered intrathecally
   
3. HOWEVER, direct GABAA receptor agonists (muscimol) does not produce analgesia at doses that do not produce motor blockade.
   
4. Experience of intrathecal benzodiazepines in man has produced mixed results.

Serotinin

1. Originates in the nucleus raphe magnus of the medulla.

Somatostatin receptor agonists

1. Somatostatin can produce non-opioid mediated intrathecal analgesia
   
2. Doses required in animals are neurotoxic.

NMDA receptor antagonists

1. NMDA receptor is activated by glutamate, but has a high threshold.
   
2. Substance P and glutamate is released by primary afferent nerves.
   
3. 
   
   1. NK-1 receptors are activated by substance P.
      
   2. AMPA receptors are activated by glutamate.
      
   3. Repeated activation of AMPA receptors and/or activation of NK-1 receptors lead to activation of NMDA receptor by glutamate.
      
   4. Activation of NMDA receptor leads to sensitization of spinal projection neurons, leading to "windup."
   5. This may lead to long lasting hyper excitable state during which non-noxious stimulation leads to pain perception (allodynia).

4. NMDA antagonist block this action. NMDA antagonists, phencyclidine-like drugs, such as ketamine and MK-801, are non-competitive antagonists.

NK-1 receptor antagonists

1. Experimental agents only. Current agents cause analgesia at doses which also lead to muscle weakness.
   
2. NK-1 receptors respond to substance P.

Prostaglandin synthesis inhibitors

1. NMDA activation leads to activation of phospholipase and the production of intracellular prostoglandins.
   
2. Spinal cord accumulation of prostoglandins leads to a hyperalgesic state.
   
3. Intrathecal NSAIDS may decrease or prevent the development of hyperalgesia and decrease pain. They may be effective in neurogenic pain.

Top