Physiology, Withdrawal Response

Article Author:
Celena Derderian
Article Editor:
Prasanna Tadi
6/14/2019 9:12:43 PM
PubMed Link:
Physiology, Withdrawal Response


Imagine that an individual accidentally steps on a sharp tack; immediately, he or she retracts that leg away from the tack. This automatic response is known as the withdrawal reflex defined as the automatic withdrawal of a limb from a painful stimulus. This reflex protects humans against tissue necrosis from contact with noxious stimuli such as pain or heat. It can occur in either the upper or lower limbs. Specifically, the withdrawal reflex mediates the flexion of the limb that comes into contact with the noxious stimuli; it also inhibits the extensors of that same limb. This reflex also promotes the extensors and inhibits the flexors of the contralateral arm or leg, virtually ensuring that the opposite limb provides stabilization. Hence, some signals can cross the midline of the spinal cord to mediate the movement of the opposite limb. This response is a polysynaptic reflex, which means that interneurons are involved in mediating the reflex between the afferent (sensory) and efferent (motor)  signals. Also, it is also an intersegmental reflex arc, meaning that the outcomes of the reflex get mediated by the stimulation or inhibition of motor neurons from multiple levels of the same spinal cord.[1] In evolution, this withdrawal response is critical in avoiding the significant dangers. 


The bodily tissue that comes into contact with noxious stimuli becomes damaged and releases chemicals that activate sensory neuron nociceptors. These chemicals include globulin and protein kinases, arachidonic acid, histamine, and prostaglandins. Nociceptors that detect tissue damage can be divided into categories. One type is called high threshold mechanonociceptors which respond to mechanical stimuli such as cutting or pinching. A second type is chemical nociceptors which react to chemicals. A third type is thermal nociceptors which respond to thermal and mechanical stimuli. There are also polymodal nociceptors that respond to chemical, thermal and mechanical stimuli. Depending on the stimulus strength, the stimulus overcomes the threshold of the sensory neuron, and an action potential initiated. The threshold represents the lowest stimulus that can evoke the depolarization of the neuron and result in an action potential. Only an action potential can signal to the central nervous system.[2]

 A sensory neuron that does get excited via its nociceptors delivers this excitation through pain fibers to the central nervous system. Notably, these fibers transmit excitation to the cell body of the sensory neuron which resides in the dorsal root ganglia of the spinal cord. The specific fibers that communicate mechanical, thermal, and chemical pain are mainly the A-delta fibers and C fibers. Once these fibers relay the action potential to the cell body of the sensory neuron in the dorsal root ganglion, the sensory neuron sends excitatory postsynaptic potentials  (EPSPs) to motor neurons and interneurons, as previously explained. The sensory neuron accomplishes this by releasing neurotransmitters; glutamate is the primary excitatory neurotransmitter in the central nervous system. Some interneurons involved in the withdrawal reflex are inhibitory and relay inhibitory postsynaptic potentials (IPSPs) by releasing inhibitory neurotransmitters; the primary inhibitory neurotransmitters in the central nervous system are glutamate and glycine.

The excited somatic motor neurons complete the withdrawal reflex by depolarizing and contracting their targeted muscles. This depolarization travels along the motor neuron, which exits the spinal cord and enters the peripheral nervous system. In the peripheral nervous system, the motor neuron releases excitatory neurotransmitter acetylcholine. Acetylcholine binds the nicotinic acetylcholine receptors on the sarcolemma of the muscle, which initiates an action potential that travels down the T-tubules. The sarcoplasmic reticulum releases calcium ions, and bind troponin, which changes its conformation. This change reveals the active site on actin, by removing tropomyosin which blocks it. Myosin now can cross-bridge to actin and induce contraction. ATP then powers the release of myosin from actin. Calcium ions are then actively transported back into the sarcoplasmic reticulum, and the tropomyosin returns to its site to block actin. The somatic motor neurons inhibited in the spinal cord will not be depolarized, resulting in no contraction of their targeted muscle groups.[3]

Organ Systems Involved

The peripheral nervous system, central nervous system, skin tissue, and musculature under activation or inhibition mediate the withdrawal reflex. Skin is the largest organ in the human body. The skin tissue is key to the entire initiation of the reflex because, when damaged, it releases chemicals to induce the activation of the sensory neurons that further the completion of the reflex. The peripheral nervous system includes the sensory neurons that are stimulated by noxious input. It also contains the somatic motor neurons that target muscles. The central nervous system is involved because the sensory neuron communicates through the spinal cord to relay the withdrawal reflex. Lastly, the muscles of the body accomplish the movement due to the reflex. Extensors and flexors complete the reflex. If the reflex were to occur in the upper limb, the flexor muscles involved include the biceps brachii and coracobrachialis at the arm. The primary extensor of the arm at the elbow joint includes the triceps brachii. In the lower limb, there are flexors at the knee include the biceps femoris, semimembranosus, and semitendinosus. Extensors of the knee include the rectus femoris, vastus lateralis, vastus medius, and vastus intermedius, together known as the quadriceps muscle group.


The withdrawal reflex begins with the sensory input of a harmful stimulus. This stimulus excites the sensory receptors, also known as nociceptors.[4] The further actions of the sensory neuron are not in chronological order but are explained in steps for clarity. Firstly, this sensory neuron sends an excitatory postsynaptic potential to a somatic motor neuron which originates in the ventral horn. An EPSP makes a postsynaptic neuron more likely to depolarize and have an action potential. This somatic motor neuron exits the ventral horn and root to stimulate the flexor muscles of the ipsilateral limb. Secondly, the sensory neuron activates an inhibitory interneuron. This interneuron sends an inhibitory postsynaptic potential a somatic motor neuron that results in the inhibition of the extensors of the ipsilateral limb. An IPSP makes a postsynaptic neuron less likely to depolarize and have an action potential. Thirdly, the sensory neuron activates an interneuron that decussates and crosses the midline of the spinal cord. Hence, the following synapses are on the contralateral side of the spinal cord. This interneuron synapses and excites a somatic motor neuron that stimulates the contralateral extensor muscles. This same interneuron that decussates also activates an inhibitory interneuron which inhibits a somatic motor neuron, resulting in the inhibition of the flexors of this contralateral limb. The accumulation of these actions results in the flexion of the limb that came into contact with the noxious stimuli and the bracing of the contralateral limb. Although these are the basic principles of the withdrawal reflex, there is more complexity to it. For example, if the reflex is resulting in the lower limbs, there are further signals that travel up the spinal cord to activate and inhibit motor neurons that control upper limb muscles. These induce needed flexion and extension of the arms to provide balance as the reflex occurs.[1]

Clinical Significance

An interruption in a specific part of the pathway of the withdrawal reflex can potentially prevent it from occurring properly; this reflex is a protective mechanism against tissue-damaging stimuli. A loss of function of sensory neurons may prevent the withdrawal reflex from being initiated. Different pathologies can affect peripheral sensation, such as multiple sclerosis and stroke. Congenital insensitivity to pain is a rare disease that impairs an individual's ability to perceive pain[5]. Insensitivity to pain makes a patient vulnerable to severe injuries due to the absence of protective reactions to noxious stimuli such as the withdrawal reflex. There are genetic variances that can alter an individual's perception of pain. These genetic variances can change sodium ion channels present in sensory neurons.[6] If motor neurons or their synapses with musculature are damaged, it may also impact the withdrawal reflex. Amyotrophic lateral sclerosis is one example of a disease that negatively affects motor neurons.[7] Autoimmune diseases such as myasthenia gravis and Lambert-Eaton syndrome negatively impact the communication between lower motor neurons and the muscles they act upon, which theoretically can alter the withdrawal reflex.[8] It is essential to study how different factors modulate the withdrawal reflex to preserve it for patients affecting neurological diseases such as these.

Specific modulators of the withdrawal reflex have been topics of research, which has revealed that the pattern of the reflex may undergo modulation by running, different phases of walking, stimulus intensity, and even the load on the leg; the particular phase of walking has even been found to reverse the reflex. Classical conditioning involving the cerebellum as a structure for procedural learning has also been found to affect the withdrawal reflex.[9][10] Non-invasive vagal nerve stimulation has also been found to increase the threshold of the withdrawal reflex to a single stimulus.[11] Stroke is the primary cause of morbidity in the United States, and stroke patients frequently exhibit spasticity as a complication, which can affect the withdrawal reflex. Research also demonstrates that injecting Botulinum toxin A modifies the withdrawal reflex in stroke patients, reducing spasticity, suggesting that Botulinum toxin A may be useful in treating post-stroke spasticity.[12]


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