LESSON 3.3 WORKBOOK. Why does applying pressure relieve pain?

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1 Postsynaptic potentials small changes in voltage (membrane potential) due to the binding of neurotransmitter. Receptor-gated ion channels ion channels that open or close in response to the binding of a neurotransmitter. LESSON 3.3 WORKBOOK Why does applying pressure relieve pain? In the last lesson, we learned how neurons send signals across the synaptic cleft via synaptic transmission. But two questions remain how does this type of signaling result in an action potential in the postsynaptic cell? And thinking back to our pain framework, how does communication between neurons in the pain pathway allow us to control how we perceive painful stimuli? The answer to both questions lies in the specialized structure at the start of the axon where the action potential originates the axon hillock. Postsynaptic potentials Remember that the local changes in membrane potential created by neurotransmitters binding to their receptors at the synaptic cleft are referred to as postsynaptic potentials. Interestingly, the kind of postsynaptic potential a particular synapse produces does not depend on the neurotransmitter itself. Instead, it is determined by the characteristics of the postsynaptic receptors the neurotransmitter binds to in particular, by the specific type of ion channel they open. Receptor-gated ion channels in the postsynaptic membrane are much more versatile than the voltage-gated ion channels in the axon. First, the postsynaptic membrane contains more than just Na + and K + channels. The postsynaptic membrane contains anion channels (permeable to negatively charged ions) as well as other cation channels (permeable to positively charged ions). Second, receptor-gated ion channels can move ions out of the postsynaptic cell as well as into it. This means that the receptor-gated ion channels can have a varied range of effects on the postsynaptic cell, as we shall see. The end goal of all these effects is on the threshold that regulates whether an action potential will fire. We can identify two major types of receptor-gated ion channels in the postsynaptic membrane: cation channels (permeable to positively charged ions) and anion channels (permeable to negatively charged ions): Two cation channels permeable to: One anion channel permeable to: What causes receptor-gated ion channels to open? How is that different from the voltagegated channels we saw in the axon? Why does opening sodium or calcium ion channels cause a neuron to depolarize? Why does opening chloride ion channels cause a neuron to hyperpolarize? Lesson 3.3 Sodium (Na + ) Chloride (Cl - ) 85 Calcium (Ca 2+ )

2 Excitatory postsynaptic potentials (EPSP) graded postsynaptic depolarizations, which increase the likelihood that an action potential will be generated. Inhibitory postsynaptic potentials (IPSP) graded postsynaptic hyperpolarizations, which decrease the likelihood that an action potential will be generated. Integration adding or combining a number of individual signals into one overall signal. Note that these channels are different from the voltage-gated sodium and calcium channels we talked about on the axon and the presynaptic terminal because they are stimulated to open by a neurotransmitter binding to its receptor, and not by a change in voltage. When channels open that are permeable to either sodium or calcium, Na + or Ca 2+ ions can enter the cell, as we saw before. This entry of positive ions depolarizes the postsynaptic membrane, making the membrane potential more positive, or phrased another way, less negative. This is called an excitatory postsynaptic potential (EPSP) and it brings the postsynaptic cell closer to the threshold for firing an action potential. However, when channels that are permeable to chloride (Cl - ) open, the negatively charged Cl - ions that are in high concentration outside the cell, are pushed inside by the force of diffusion. This entry of negative ions hyperpolarizes the postsynaptic membrane, making the membrane potential more negative. This is called an inhibitory postsynaptic potential (IPSP) and it brings the postsynaptic cell farther away from the threshold to fire an action potential. Threshold Voltage at which Na + channels open Inhibitory Postsynap/c poten/als (IPSP) caused either by entry of Cl - ions, or exit of K + ions Excitatory Postsynap/c poten/als (EPSP) caused by entry of either Na + or Ca 2+ ions Figure 7: Getting to threshold. IPSPs decrease the chance of reaching threshold because they make the membrane potential more negative. EPSPs increase the chance of reaching threshold because they make the membrane potential more positive. Recall that an action potential is only initiated after the threshold that opens the axon s voltage-gated Na + channels is reached. Because EPSPs depolarize the postsynaptic membrane, they bring the membrane potential closer to threshold, increasing the likelihood that the voltage-gated Na + channels will open and the postsynaptic neuron will fire an action potential. Conversely because IPSPs hyperpolarize the postsynaptic membrane they move the membrane potential further away from threshold, decreasing the likelihood the voltage-gated Na + channels will open and the postsynaptic neuron will fire an action potential. (Figure 7). Remember though that a single dendritic tree may have hundreds of thousands of synapses, all of which receive inputs from presynaptic terminals. What happens when an EPSP and an IPSP arrive at the same time close to each other? Do they simply cancel each other out in the membrane? Obviously this isn t a good solution and each neuron has the job of integrating all these many different types of inputs into a coherent output. They do this through the process of integration. Why do EPSPs increase the likelihood of firing an action potential? Why do IPSPs decrease the likelihood of firing an action potential? Lesson

3 Axon hillock specialized part of a neuron s cell body that connects to the axon. As a result, the initial segment or axon hillock is the site where action potentials originate. The integration of all local postsynaptic potentials (EPSPs and IPSPs) occurs in the axon hillock (Figure 8). The goal of input integration is to put the neuron into a final electrical state whereby it can either fire an action potential or not. Generally: Excitatory Synapse: Neurotransmi4ers open Na + or Ca 2+ channels producing EPSPs. Inhibitory Synapse: Neurotransmi4ers open either K + or Cl - channels producing IPSPs. Axon hillock reaches threshold and acdon potendal is fired. IPSPs encounter EPSPs. Threshold is not reached and no acdon potendal is fired. Figure 8: Axon hillock. The axon hillock generates an action potential if the excitatory inputs reach threshold to open the voltage-gated Na + channels. The axon hillock will not generate an action potential if the inputs do not reach the threshold to open the voltage-gated Na + channels. The axon will only fire an action potential if the postsynaptic membrane reaches the threshold to open the axon s voltage-gated Na + channels. This can only happen when the excitatory inputs are greater than the inhibitory inputs. The axon will not fire an action potential if the postsynaptic membrane does not reach the threshold to open the axon s voltage-gated Na + channels. This happens when the excitatory inputs aren t great enough, and/or when the inhibitory inputs are greater than the excitatory inputs. The process of synaptic integration is in continuous operation in every neuron in the nervous system. Each cell integrates all of the synaptic information it receives at any one time, and depending on the balance of excitation and inhibition, it either fires an action potential or it doesn t. Under what circumstances will the axon hillock initiate an action potential? Under what circumstances will the axon hillock not initiate an action potential? Why? To further explore this idea let s examine how applying pressure can relieve pain, but before we dive into Lesson 3.3 that discussion, let s first remind ourselves of the pathway to get pain to the brain. 87

4 Projection neuron neuron whose axons make synapses in the brain. The pain synapse in the spinal cord Recall that the pain pathway has four neurons. The first is in the periphery, the second is in the spinal cord, the third is in the thalamus, and the fourth is in the somatosensory cortex. Let s take a closer look at the synapse between the first neuron and the second in the spinal cord. In the spinal cord, neurons carrying pain stimuli make synaptic connections within the grey matter in the area that deals with sensory information called the dorsal horn. Specifically, the first pain neurons connect to projection neurons that then project up the spinal cord, carrying pain information to the third neuron in the thalamus (Figure 9). But the first pain neurons aren t the only neurons that make connections with the projection neurons. A different type of neuron that is sensitive to pressure, not to pain, also connects with the same projection neuron (Figure 9). We call these connections between pain, pressure and projection neurons a circuit. This circuit is the first way we manage our responses to painful stimuli. We can diagram how the circuit is wired (Figure 10). How the circuit works Now that we know how the circuit is wired, let s look at how it works. Figure 9: Pain and pressure synapse in the spinal cord. Neurons carrying painful information, as well as neurons carrying pressure information both synapse on the same projection neuron that carries information to the brain. Remember, that the neurons carrying painful stimuli synapse on the projection neurons. These pain neurons make excitatory synapses with projection neurons. This means that when pain neurons are activated What is the benefit of having both pain and pressure sensitive neurons synapsing on the same projection neuron? How does applying pressure relieve some of our pain? by painful stimuli they will always excite the projection neurons to produce an action potential. Lesson Interneuron Pain neuron Pressure neuron Projec-on neuron To Brain Figure 10: Wiring of pain and pressure synapse in the spinal cord.

5 Behavioral inhibition inhibition of behavior. Neural inhibition inhibition of neural signaling. However, remember that the projection neurons are also connected to pressure sensitive neurons. But these neurons make inhibitory synapses with the projection neurons. This means that when pressuresensitive neurons are activated by pressure stimuli, they will always inhibit the projection neurons, preventing them from producing an action potential. We can see this circuit in action when we bang our elbow or stub our toe, and then immediately go to rub it. By rubbing the painful area we re applying pressure that will activate our pressure-sensitive neurons. These neurons will then communicate with the projection neurons in the spinal cord and inhibit them so they ll no longer tell the brain that they re getting painful information from the first pain neurons. It s all a matter of balancing excitatory and inhibitory inputs. It s not quite the same as No brain, no pain, but if the pain never gets to the brain, we certainly can t feel it. Excitation vs Inhibition It s just a bit more complicated Note that an inhibitory postsynaptic potential, which leads to neural inhibition, does not always produce behavioral inhibition. For example, suppose a group of neurons actually prevents a particular movement from taking place, for instance if they hold your head erect, preventing it from falling forward. If these neurons experience enough IPSPs they won t fire an action potential and will experience neural inhibition. But what effect will this have on your head? In fact if these neurons are inhibited, i.e. prevented from functioning, they will no longer be able to prevent your head falling onto your chest. Thus, inhibiting inhibitory neurons makes the behavior more likely to occur. If we think about neural excitation we can see that the same thing occurs: If we activate neurons that inhibit a behavior, we will tend to suppress that behavior. For example, when we are dreaming, a particular set of inhibitory neurons in the brains becomes active and prevents us from getting up and acting out our dreams. It is important to remember that all neurons need to reach threshold before they can fire an action potential and communicate with other neurons via synaptic transmission. Whether they will reach that threshold depends on how the axon hillock integrates the hundreds of thousands of excitatory and inhibitory inputs that fall onto the dendritic tree. If the action potential is fired, whether that neuron will have an excitatory or inhibitory effect on the postsynaptic cells it communicates with will depend on which neurotransmitters it releases, how they interact with their receptors on the postsynaptic side and which ion channels they open. In summary, an action potential always precedes synaptic transmission, and an action potential is always preceded by reaching threshold, and to reach threshold more excitatory inputs than inhibitory inputs are required (even if the neuron is inhibitory). Can you predict the effects of damage to our neurons that prevent us acting out our dreams? Lesson

6 STUDENT RESPONSES What must always precede the release of neurotransmitter? Remember to identify your sources What must always precede the firing of an action potential? Therefore, even in the case of an inhibitory neuron, what sequence of events must occur before it can release neurotransmitter to inhibit the postsynaptic cell? Lesson