anatomy exam part 3 Flashcards
•Nociceptors are
•Pain and nociception
- Pain - feeling of sore, aching, throbbing
- Nociception - sensory process, provides signals that trigger pain
- The receptors for pain are free nerve endings in the skin, muscle, and viscera.
Describe the initial molecules in the inflammatory factors that can activate nociceptor receptors
§Damaged cells release substances that open ion channels
- Proteases (-> bradykinin), Substance P,
- Histamine
- Prostaglandin
Capsaicin
Capsaicin is a chemical compound that was first isolated from chili peppers in crystalline form in 1878. Soon after, it was discovered that capsaicin caused a burning sensation in the mucous membranes. In addition, it increased secretion of gastric acid and stimulated the nerve endings in the skin.
•Thermoreceptors
§“Hot” and “cold” receptors
§Varying sensitivities
Trpv 2 hotest
Describe the fast and slow pains and the fibers mediating them; A=acute, fast; C=chronic, slow
•Primary Afferents and Spinal mechanisms
§First pain and second pain
§First pain: brief, pricking, well-organized
§Second pain: long lasting, burning, less organized
A fiber : first pain
C fiber: second pain
- Describe how opioid peptides work pre-synaptically and post-synaptically
- Describe how opioid peptides work pre-synaptically and post-synaptically
- possible direct actions of opiods on peripheral tissue
- inhibition occurs at the spinal cord
- opiod is on GABA and attaches to pain inhibotory neuron in medulla - possible site of action: diencephalon [ventral caudal thalamus]
- Allodynia can lead to the triggering of a pain response from?
- Hyperalgesia is an increased sensitivity to ?
- stimuli which do not normally provoke pain.
- pain
- Classic migraine
- Common migraine
Ocular Migraine
•Classic migraine
§With Aura
§Aka Neurologic migraine
§Disturbance of neurologic functions
§Aura: scintillating dots or shapes
§Headache develops in 10-30 min, then intensifies, and lasts several hours to days
•Common migraine
§With NO Aura
§Headache develops with no warning signs, then intensifies, and last several hours to days
§Ratio to classic migraine 5:1
•Ocular Migraine: neurologic dysfunction to one eye
Describe trigeminothalamic tract and migraine pain pathophysiology
•Conveys nerve impulses for most somatic sensations from the face, nasal cavity, oral cavity and teeth to the cerebral cortex.
right brain controls left side of body and vice versa
Nociceptive input from the meningeal vessels;
Sensory afferents from the head travel as trigeminal afferents through Trigeminal ganglion (TGG) like DRG in spinal cord);
Synapse on second-order neurons in the trigeminocervical complex (TCC) in brain stem.
Neurons in TCC in turn project in the quintothalamic tract and, after decussating in the brainstem, synapse on neurons in the thalamus.
There is a reflex connection between neurons in the pons (SuS, the superior salivatory nucleus), which results in a cranial
…cranial parasympathetic outflow that is mediated through the pterygopalatine ganglia (PG, also called sphenopalatine ganglion, SPG).
This trigeminal–autonomic reflex is present in normal persons and is expressed most strongly in cluster headache; and may be active in migraine.
Trigeminal nociceptive input is subject to descendinginhibitory modulation from the PAG, A11 dopaminergic center, locus ceruleus (LC), and raphe nuclei (not shown) magnus (Red pathway).
- Describe the current theory of migraine pain pathophysiology and explain how triptans work (including how CGRP signaling leads to blood vessel dilation and triptans work on 5HT1 leading to constriction)
- Migraine is best understood as a primary disorder of the brain.
- Migraine is not caused by a primary vascular event.
- It is a form of neurovascular headache: a disorder in which neural events result in the dilation of blood vessels, which, in turn, results in pain and further nerve activation.
-We may consider the basic biologic problem in migraine to be the dysfunction of an ion channel in the aminergic brain-stem nuclei that normally modulates sensory input and exerts neural influences on cranial vessels
- Imbalance in the brainstem results in
- Activation of the perivascular trigeminal nerves that release
- Central pain transmission may activate other brainstem nuclei, resulting in
- The antimigraine effects of the 5-HT 1B/ID receptor agonists are
- •Imbalance in the brainstem results in vasodilation of intracranial extracerebral blood vessels
- •Activation of the perivascular trigeminal nerves that release vasoactive neuropeptides (neurokinin, substance P, CGRP etc) to promote neurogenic inflammation.
- •Central pain transmission may activate other brainstem nuclei, resulting in associated symptoms (nausea, vomiting, photophobia, phonophobia).
- •The antimigraine effects of the 5-HT 1B/ID receptor agonists are highlighted at areas 1, 2, and 3. (CGRP, calcitonin gene-related peptide.)
Migraine is a neurological disorder that is caused
Describe the gene mutations discovered for migraines
Migraine is a neurological disorder that is caused by increased excitability of the CNS.
Mutations affecting the central glutamate synapse
Increased Ca2+ influx caused by familial hemiplegic migraine subtype 1 (FHM1) associated mutations in Cav2.1 channels enhance glutamate release from presynaptic terminals. Loss of Na+/K+ ATPase function, as seen in FHM2, indirectly reduces astrocyte uptake of glutamate, resulting in increased levels of the neurotransmitter in the synaptic cleft
TCC: trigeminocervical complex
SSN: superior salivatory nucleus
SPG: sphenopalatine ganglion
TCC: C1 and C2 regions of the spinal cord, collectively known as the trigeminocervical complex (TCC) is thought to explain the common distribution of pain in migraine.
The superior salivatory nucleus (or nucleus salivatorius superior) of the facial nerve.
The sphenopalatine ganglion (SPG) is a nerve bundle behind the bony structure of the nose that has been long recognized to be associated with pain pathways of certain headache disorders, such as cluster headache.
How does CGRP cause vasodilation?
- CGRP=Calcitonin gene-related peptide
- Release of neuropeptides such as CGRP is a pivotal aspect of migraine.
- CGRP is a powerful vessel dilator, working through G protein coupled receptor GPCR, which activates the cAMP pathway.
- CGRP can induce the release of histamine, amplifying the inflammation.
- Direct inhibition of CGRP receptor by antagonist (called small molecule gepants) or direct binding of CGRP by mAbs) is also used to treat migraine in clinical trials. Drugs in pipeline.
How does 5-HT cause vasoconstriction?
- cAMP pathway leads to smooth muscle relaxationàvasodilation.
- 5-HT1 receptors are Gi coupled receptors.
- Inhibition by Gi proteins decreases cAMP so decrease muscle relaxation and enhances muscle contractionà vasoconstriction.
5-HT1D/1B autoreceptor activation (presynaptic) reduces CGRP release at
periphery.
Gs, Gi, Gq pathways and contraction or relaxation
In cardiac muscle, b1 receptor action leads to contraction;
In respiratory smooth muscle, b2 receptor activation leads to relaxation;
In smooth muscle, a1 and a2 receptor activation leads to contraction;
Smooth muscle contraction=constriction
cAMP in smooth muscle causes relaxation
Cardiac, beta 1 contraction
Smooth, beta 2 Relaxation
