1. W5D3H4: Pain and Reflexes
Note W5D3H4 is also in this note set, starting on slide 30. There is a GRAT group activity in between.

2. Learning Objectives
1. Describe pain sensory pathways and relevant molecules involved in nociception.
2. Outline spinal reflex circuits, including those activated in the presence of a painful stimulus.
3. Describe the clinical use of reflexes as assays of motor neuron function and relate changes in pain and somatic detection to diabetic neuropathies.

3. LO 1. Describe pain sensory pathways and relevant molecules involved in nociception
nocioceptors
Area on the skin that receptor responds to
rapidly adapting
slowly adapting
rapidly adapting
slowly adapting

4. Anatomy of nociceptors
LO 1. Describe pain sensory pathways and relevant molecules involved in nociception
Anatomy of nociceptors
(A) Somatosensory neurons are located in peripheral ganglia (trigeminal and dorsal root ganglia) located alongside the spinal column and medulla. Afferent neurons project centrally to the brainstem (Vc) and dorsal horn of the spinal cord and peripherally to the skin and other organs. Vc, trigeminal brainstem sensory subnucleus caudalis. (B) Most nociceptors are unmyelinated with small diameter axons (C-fibers, red). Their peripheral afferent innervates the skin (dermis and/or epidermis) and central process projects to superficial laminae I and II of the dorsal horn. (C) A-fiber nociceptors are myelinated and usually have conduction velocities in the Aδ range (red). A-fiber nociceptors project to superficial laminae I and V.

5. LO 1. Describe pain sensory pathways and relevant molecules involved in nociception
Compound action potentials recoded in response to peripheral nerve stimulation
Conduction latency

6. LO 1. Describe pain sensory pathways and relevant molecules involved in nociception

7. LO 1. Describe pain sensory pathways and relevant molecules involved in nociception
Known or proposed transduction mechanisms in mammalian nociceptor peripheral terminals.
heat
cold
Ion channels that transduce heat (A), cold (B), and mechanical stimuli (C) are depicted. Stimuli are presented to the skin, which is depicted as containing representative nonneuronal cells (such as keratinocytes) (brown cells) and the free nerve endings of nociceptor axons (blue). Arrows next to channels indicate whether their activity is increased or decreased upon stimulation. Note that these nocisensors are not necessarily coexpressed in the same terminal. The curved arrow in C refers to the transducer(s) and other channels and molecules that contribute to the firing pattern (e.g., rapidly adapting vs. slowly adapting) in these fibers. Molecularly unidentified channels with indicated ion permeabilities inside drawing of channel are referred to as “putative RA MA channel” and “putative IA/SA MA channel.” MA, mechanically activated; RA, rapidly adapting; IA, intermediate adapting; SA, slowly adapting.
pressure

8. LO 1. Overview of pain response to mechanical injury: Release of protease -> Bradykinin production -> activation of free nerve endings-> action potential propagated to spinal cord & axonal branches-> nociceptor axons release substance P and CGRP -> histamine release -> vasodilation and increased pain sensation.
Consider drawing this out or asking students to draw it out.
Some of the main components of the 'inflammatory soup' are shown, including peptides (bradykinin), lipids (prostaglandins), neurotransmitters (serotonin (5-HT) and ATP) and neurotrophins (NGF). Each of these factors sensitize (lower the threshold) or excite the terminals of the nociceptor by interacting with cell-surface receptors expressed by these neurons. Examples of these factors and representative molecular targets are indicated in the box. Activation of the nociceptor not only transmits afferent messages to the spinal cord dorsal horn (and from there to the brain), but also initiates the process of neurogenic inflammation. This is an efferent function of the nociceptor whereby release of neurotransmitters, notably substance P and calcitonin gene related peptide (CGRP), from the peripheral terminal induces vasodilation and plasma extravasation (leakage of proteins and fluid from postcapillary venules), as well as activation of many non-neuronal cells, including mast cells and neutrophils. These cells in turn contribute additional elements to the inflammatory soup.
Kininogen: Made in liver, endothelial cells, platelets, and neutrophil. Involved in inflammation and coagulation.

9. NINDS Reflex Assessment Scale
LO2. Outline spinal reflex circuits, including those activated in the presence of a painful stimulus.
"Striking the tendon below the patella gives rise to a sudden extension of the leg, known
as the knee-jerk reflex.”
Sir Michael Foster (1877) Textbook of Physiology
NINDS : Neurological Disorders and Stroke Scale
NINDS Reflex Assessment Scale
0 Reflex absent
Reflex small, less than normal; includes a trace response or a response brought out only with reinforcement
2 Reflex in lower half of normal range
3 Reflex in upper half of normal range
4 Reflex enhanced, more than normal; includes clonus

10. Short latency (< 40 ms) Stereotyped responses
LO2. Outline spinal reflex circuits, including those activated in the presence of a painful stimulus.
Characteristics of Spinal reflexes
Involuntary
Short latency (< 40 ms)
Stereotyped responses
Only require peripheral and spinal neurons
This should be review

11. Physiological Mechanisms Underlying Spinal Reflexes
LO2. Outline spinal reflex circuits, including those activated in the presence of a painful stimulus.
This should be review
Physiological Mechanisms Underlying Spinal Reflexes

12. This should be review

13. LO2. Outline spinal reflex circuits, including those activated in the presence of a painful stimulus.
A more complicated reflex involving flipping the signal when crossing the spinal cord chiasm.

14. LO2. Outline spinal reflex circuits, including those activated in the presence of a painful stimulus.
Flexion and Crossed-Extensor Reflexes in arms
A more complicated reflex involving flipping the signal when crossing the spinal cord chiasm.
Pain!!!

15. 0+ No response or absent reflex 1+ Trace or decreased response
LO 3. Describe the clinical use of reflexes as assays of motor neuron function and relate changes in pain and somatic detection to diabetic neuropathies.
The type or intensity of reflexes are graded according to the following criteria:
Grade Response
0+  No response or absent reflex
1+  Trace or decreased response
2+ Normal response
3+ Exaggerated or brisk response
4+ Sustained response
Damage to spinal motor neurons, defects in synaptic transmission at the NMJ or muscle atrophy can result in grades of 0 or 1.
Grades of 3 or 4 can be indicative of damage to the spinal cord or brain, which result in a condition known as ‘spasticity’ and may include clonus.
Project this slide and briefly review it with students.

16. LO 3. Describe the clinical use of reflexes as assays of motor neuron function: Spasticity
Spasticity is a condition characterized by hypertonicity (increased muscle tone), clonus (a series of rapid muscle contractions), exaggerated tendon jerk reflexes, involuntary muscle spasms, scissoring (involuntary crossing of the legs), and stiff joints caused by co-contraction of antagonist muscles.
The degree of spasticity varies from mild muscle stiffness to severe, painful, and uncontrollable muscle spasms. Spasticity can interfere with rehabilitation in patients with certain disorders, and often interferes with daily activities.
Spasticity is usually caused by damage to brain or spinal neurons involved in the control of movement. It may occur in association with spinal cord injury, multiple sclerosis, cerebral palsy, anoxia, brain trauma, severe head injury, and diseases such as adrenoleukodystrophy, amyotrophic lateral sclerosis (ALS), and phenylketonuria.
Inferences drawn from an animal model suggest that one of the principal mechanisms of spasticity is an increase in the excitability of motoneurons consequent to the lesion in the brain or spinal cord. The increased excitability results in sustained repetitive discharge of motoneurons in response to brief stimuli.
Differential: Clasp knife (UMN damage) vs. Lead pipe rigidity (Basal ganglion dysfunction)
A useful distinction when encountering muscle rigidity is between clasp knife rigidity, where resistance melts away with passive stretch and lead pipe rigidity, where the resistance is uniform across the reflex arc.

17. LO 3. Describe the clinical use of reflexes as assays of motor neuron function:
Clasp-Knife Reflex
The clasp-knife reflex (also called the inverse myotatic reflex) is a pathological reflex that is only observed following lesions of the central nervous system that produce spasticity.
In response to a rapid muscle stretch, a patient with spasticity first exhibits a strong stretch reflex, followed by a relaxation of the muscle. It is the sudden release of muscle tension when a contracting muscle is forcibly stretched that gives the reflex its name: The spastic limb initially resists flexion (because of the stretch reflex) and then collapses on itself like the blade of a jack- or clasp-knife.
The reflex is thought to be mediated by group II and group III afferent fibers arising from free nerve ending receptors located in muscle fascia and aponeuroses.
The spinal circuits responsible for the clasp-knife reflex are normally suppressed and only become operational only after lesions to the spinal cord or brain.
Differential: Clasp knife (UMN damage) vs. Lead pipe rigidity (Basal ganglion dysfunction)
A useful distinction when encountering muscle rigidity is between clasp knife rigidity, where resistance melts away with passive stretch and lead pipe rigidity, where the resistance is uniform across the reflex arc.

18. Clonus is the result of a reverberating or exaggerated response
The following is a good way to conceptualize clonus: If a person standing on the tip ends of the feet suddenly drops his or her body downward and stretches the gastrocnemius muscles, stretch reflex impulses are transmitted from the muscle spindles.
Normally this helps you to not land on your heels too hard- as you are able, stand up and try it!
In clonus, these impulses reflexively excite the stretched muscle, which lifts the body up again. After a fraction of a second, the reflex contraction of the muscle dies out and the body falls again, thus stretching the spindles a second time.
Again, a dynamic stretch reflex lifts the body, but this too dies out after a fraction of a second, and the body falls once more to begin a new cycle. In this way, the stretch reflex of the gastrocnemius muscle continues to oscillate, often for long periods.
Clonus movie:
Watch the movie. Ask students to stand up and demonstrate the reflex.

19. Babinski sign
A reflex in which there is extension upward of the toes and the abduction of the toes when the sole of the foot is stroked firmly on the outer side from the heel to the front
Normal in infants under the age of 2 years but a sign of brain or spinal cord injury or disease in older persons.
Babinski is a very important reflex that changes as we develop. In infants a positive response is normal but after ~2 it is a sign of upper motor neuron damage.
Watch