Response to Dr Foreman’s questions
a. Discuss the nociceptive mechanisms, including the postsynaptic receptors of the spinal neurons, transmitters, pathways and nuclei that are activated when the injury occurs. Also include in your answer the explanation for the sharp pain and the long lasting pain that you experience with this injury.
Nociceptors are specialized peripheral sensory neurons that are activated by noxious stimuli. These nociceptors are the free nerve endings of primary sensory neurons. Upon tissue injury, in this case the stomping on the big toe, the noxious stimuli causes tissue damage. The damaged tissues in the big toe releases a host of substances including prostaglandins, bradykinins, substance P, ATP, acetylcholine, serotonin and histamine amongst others. These noxious stimuli depolarize the bare nerve endings of the afferent axons leading to the generation of action potentials (Kandel et al, 2013). Action potentials are generated because the nociceptor membranes contain receptors that convert the energy of the noxious stimuli into depolarizing electrical potentials (Kandel et al, 2013). It has been shown that activation of these receptors results in the production of second messengers and downstream activation of protein kinases and phospholipases. The second messengers regulate the activity of many receptors and ion channels[1]. Voltage gated ion channels like sodium (Na+), calcium (Ca2+) and chloride (Cl-) open and contribute to the depolarizing wave that generates the action potentials[2]. Closure of potassium (K+) channels can also lead to depolarization[2]. The resulting action potential transmits the information on the axons of the nociceptive neuron to the spinal cord. Indeed the central branches of most nociceptors terminate in the dorsal horn of the spinal cord[3]. Upon reaching the presynaptic terminal in the dorsal horn, the action potential leads to elevation of calcium (Ca2+) levels in the presynaptic terminal leading to the release of the excitatory neurotransmitter, Glutamate from the axon terminals into the synapse. …show more content…
The released Glutamate binds to and activates receptors in the postsynaptic nerve terminal (the dorsal horn neuron)[1]. Specifically activation of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type and N-methyl-D-aspartate (NMDA)-type glutamate receptors lead to depolarization and the generation of action potentials which transmits the pain impulses through ascending pathways (e.g. spinothalamic tract ) to the brain. Neuropeptides like substance P are also released into the synapse and have been shown to prolong the depolarization wave elicited by Glutamate (Kandel et al, 2013). The transmission of the signal results in elevated release of norepinephrine from the locus coeruleus neurons which project to the thalamus. This in turn relays the nociceptive signal to the somatosensory cortex, hypothalamus and hippocampus[4, 5].
Parts of the brain shown to be involved in decoding the pain stimulus to cause perception include the thalamus, sensory cortex, reticular formation and hypothalamus. The somatosensory cortex identifies the location and intensity of the pain. The brain also modulates the pain response through the use of inhibitory neurotransmitters like GABA and glycine.
Figure 1 summarizes the processes described above. (Please find Fig 1 attached as a pdf). The initial sharp pain and long lasting pain that is experienced with the injury can be explained by the different nociceptors that exist in the toe and other areas of the periphery. In general nociceptors are mainly unmyelinated or thinly myelinated. The nociceptors involved in the kind of pain experienced are thermal, mechanical or polymodal. Mechanical and thermal nociceptors are the peripheral endings of thinly myelinated Aδ fibers whilst polymodal nociceptors have unmyelinated C fibers. Aδ fiber axons are thinly myelinated and therefore are able to conduct action potentials faster than the C fibers. The first sharp pain (so called ‘first pain’) felt is transmitted by Aδ fibers which carry information from the damaged mechanical and thermal nociceptors. The long lasting pain(so called ‘slow dull pain’) felt is transmitted by the slower C fibers that carry signals from polymodal nociceptors[2]. It has been shown that perception of pain results when the stimulation of nociceptors is intense enough to activate Aδ fibers leading to the initial sharp pain[6]. With stimulus strength increase, C fibers are recruited resulting in the experience of long lasting pain which persists even when the stimulus ceases[3, 6]. b. What occurred in the nervous system to reduce the pain
a. Discuss the nociceptive mechanisms, including the postsynaptic receptors of the spinal neurons, transmitters, pathways and nuclei that are activated when the injury occurs. Also include in your answer the explanation for the sharp pain and the long lasting pain that you experience with this injury.
Nociceptors are specialized peripheral sensory neurons that are activated by noxious stimuli. These nociceptors are the free nerve endings of primary sensory neurons. Upon tissue injury, in this case the stomping on the big toe, the noxious stimuli causes tissue damage. The damaged tissues in the big toe releases a host of substances including prostaglandins, bradykinins, substance P, ATP, acetylcholine, serotonin and histamine amongst others. These noxious stimuli depolarize the bare nerve endings of the afferent axons leading to the generation of action potentials (Kandel et al, 2013). Action potentials are generated because the nociceptor membranes contain receptors that convert the energy of the noxious stimuli into depolarizing electrical potentials (Kandel et al, 2013). It has been shown that activation of these receptors results in the production of second messengers and downstream activation of protein kinases and phospholipases. The second messengers regulate the activity of many receptors and ion channels[1]. Voltage gated ion channels like sodium (Na+), calcium (Ca2+) and chloride (Cl-) open and contribute to the depolarizing wave that generates the action potentials[2]. Closure of potassium (K+) channels can also lead to depolarization[2]. The resulting action potential transmits the information on the axons of the nociceptive neuron to the spinal cord. Indeed the central branches of most nociceptors terminate in the dorsal horn of the spinal cord[3]. Upon reaching the presynaptic terminal in the dorsal horn, the action potential leads to elevation of calcium (Ca2+) levels in the presynaptic terminal leading to the release of the excitatory neurotransmitter, Glutamate from the axon terminals into the synapse. …show more content…
The released Glutamate binds to and activates receptors in the postsynaptic nerve terminal (the dorsal horn neuron)[1]. Specifically activation of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type and N-methyl-D-aspartate (NMDA)-type glutamate receptors lead to depolarization and the generation of action potentials which transmits the pain impulses through ascending pathways (e.g. spinothalamic tract ) to the brain. Neuropeptides like substance P are also released into the synapse and have been shown to prolong the depolarization wave elicited by Glutamate (Kandel et al, 2013). The transmission of the signal results in elevated release of norepinephrine from the locus coeruleus neurons which project to the thalamus. This in turn relays the nociceptive signal to the somatosensory cortex, hypothalamus and hippocampus[4, 5].
Parts of the brain shown to be involved in decoding the pain stimulus to cause perception include the thalamus, sensory cortex, reticular formation and hypothalamus. The somatosensory cortex identifies the location and intensity of the pain. The brain also modulates the pain response through the use of inhibitory neurotransmitters like GABA and glycine.
Figure 1 summarizes the processes described above. (Please find Fig 1 attached as a pdf). The initial sharp pain and long lasting pain that is experienced with the injury can be explained by the different nociceptors that exist in the toe and other areas of the periphery. In general nociceptors are mainly unmyelinated or thinly myelinated. The nociceptors involved in the kind of pain experienced are thermal, mechanical or polymodal. Mechanical and thermal nociceptors are the peripheral endings of thinly myelinated Aδ fibers whilst polymodal nociceptors have unmyelinated C fibers. Aδ fiber axons are thinly myelinated and therefore are able to conduct action potentials faster than the C fibers. The first sharp pain (so called ‘first pain’) felt is transmitted by Aδ fibers which carry information from the damaged mechanical and thermal nociceptors. The long lasting pain(so called ‘slow dull pain’) felt is transmitted by the slower C fibers that carry signals from polymodal nociceptors[2]. It has been shown that perception of pain results when the stimulation of nociceptors is intense enough to activate Aδ fibers leading to the initial sharp pain[6]. With stimulus strength increase, C fibers are recruited resulting in the experience of long lasting pain which persists even when the stimulus ceases[3, 6]. b. What occurred in the nervous system to reduce the pain