Introduction

The withdrawal response (reflex), also known as the nociceptive flexion reflex, is an automatic response of the spinal cord that is critical in protecting the body from harmful stimuli. The first known definition of a reflex dates back to 1649 when René Descartes noted that specific bodily movements occurred instantaneously and independent of the process of thought. Modern definitions state that a reflex is an involuntary response of effector tissue caused by the stimulation of specific receptors.[1] 

The reflex arc is the basic unit of a reflex, which involves neural pathways acting on an impulse before that impulse has reached the brain. Instead of directly traveling to the brain, sensory neurons of a reflex arc synapse in the spinal cord. This is an important evolutionary adaptation for survival, which allows faster actions by activating spinal motor neurons instead of delaying reaction time by signals first having to go to the brain.

The withdrawal reflex can occur in either the upper or lower limbs and is a polysynaptic reflex, which means that interneurons mediate the reflex between the afferent (sensory) and efferent (motor) signals. In contrast, the deep tendon reflex is monosynaptic and does not utilize interneurons to transmit information. Additionally, the withdrawal response is an intersegmental reflex arc, meaning that the outcomes of the reflex are mediated by the stimulation or inhibition of motor neurons from multiple levels of the same spinal cord.[2]

Cellular Level

Body tissues that come into contact with noxious stimuli become damaged and release chemicals that activate sensory neuron nociceptors. These chemicals include globulin and protein kinases, arachidonic acid, histamine, and prostaglandins. Nociceptors detect tissue damage and can be divided into categories, including high threshold mechanonociceptors which respond to mechanical stimuli (e.g., cutting or pinching); chemical nociceptors, which respond to injury-related chemical stimuli, and thermal nociceptors, which respond to thermal and mechanical stimuli. In addition, polymodal nociceptors exist that respond to chemical, thermal, and mechanical stimuli.[3] If the strength of a stimulus is great enough, it can overcome the sensory neuron threshold, and an action potential can be initiated. The threshold represents the lowest stimulus that can evoke the depolarization of the neuron and result in an action potential.[4]

A sensory neuron that gets excited via its nociceptors delivers this excitation through pain fibers to the central nervous system (CNS). Notably, these fibers transmit excitation to the cell body of the sensory neuron, which resides in the dorsal root ganglia (DRG) of the spinal cord. The specific fibers that communicate mechanical, thermal, and chemical pain are the A-delta and C fibers. Once these fibers relay the action potential to the cell body of the sensory neuron in the DRG, the sensory neuron sends excitatory postsynaptic potentials (EPSPs) to motor neurons and interneurons, as previously explained. The sensory neuron accomplishes this by releasing neurotransmitters, with glutamate being the primary excitatory neurotransmitter in the CNS. Some interneurons involved in the withdrawal reflex are inhibitory and relay inhibitory postsynaptic potentials (IPSPs) by releasing inhibitory neurotransmitters, with the primary inhibitory neurotransmitters in the CNS being GABA and glycine.[5]

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 (PNS). Within the PNS, the motor neuron releases the excitatory neurotransmitter acetylcholine (ACh), which binds to the nicotinic acetylcholine receptors on the sarcolemma of the muscle, initiating an action potential that travels down the T-tubules. The sarcoplasmic reticulum (SR) then releases calcium ions and binds troponin, changing its conformation. This change reveals the active site on actin by removing tropomyosin, and myosin can now form a cross-bridge with actin to induce contraction. ATP then powers the release of myosin from actin, calcium ions are actively transported back into the SR, and 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.[6]

Organ Systems Involved

The withdrawal reflex is mediated by the PNS and CNS, the epidermis, and the musculoskeletal system. The epidermis is central to the reflex initiation because, when damaged, it releases chemicals to induce the activation of the sensory neurons that further the completion of the reflex. The PNS includes the sensory neurons stimulated by noxious input and the somatic motor neurons that target muscles. The CNS is involved because the sensory neuron communicates through the spinal cord to relay the withdrawal reflex. Lastly, the extensor and flexor muscles of the body accomplish the actual movement of the limb away from the stimulus. For example, suppose the reflex was to occur in the upper limb. In this case, the flexor muscles involved include the biceps brachii and coracobrachialis, with the primary extensor of the arm at the elbow joint being the triceps brachii. In the lower limb, there are flexors at the knee, which include the biceps femoris, semimembranosus, and semitendinosus muscles. Extensors of the knee include the rectus femoris, vastus lateralis, vastus medius, and vastus intermedius, collectively known as the quadriceps muscle group.

Function

The withdrawal reflex protects humans against tissue necrosis from contact with noxious stimuli such as pain or heat and is evolutionary important in avoiding significant dangers.

Mechanism

The withdrawal reflex is polysynaptic, meaning that, in addition to the sensory and motor neurons, this response utilizes interneurons which pass signals between the sensory and motor neurons, ultimately creating multiple synaptic connections.[7] The steps of a polysynaptic withdrawal reflex are outlined below, resulting in a limb pulling away from the noxious stimulus within half a second.

1. Nociceptors, receptors specialized to detect noxious stimuli, detect a painful stimulus.[8]
2. Activation of nociceptors allows an action potential to occur in a sensory neuron.
3. This sensory neuron sends an excitatory postsynaptic potential (EPSP) to a somatic motor neuron within the ventral horn of the spinal cord, activating multiple reflex pathways.
4. One pathway involves the somatic motor neuron exiting from the ventral horn to stimulate the flexor muscle of the ipsilateral limb, causing it to withdraw from the painful stimulus.
5. Another pathway involves the sensory neuron activating an inhibitory interneuron, which sends an inhibitory postsynaptic potential (IPSP) to a somatic motor neuron that results in the inhibition of the extensors of the ipsilateral limb.
6. Additionally, a sensory neuron activates an interneuron that decussates and crosses the spinal cord's midline, inhibiting the motor neuron that usually activates the opposing extensor muscle in the limb. This keeps the extensor muscle from counteracting the attempt of the flexor muscle to pull the limb away. This interneuron synapses and excites a somatic motor neuron that stimulates the contralateral extensor muscles. This is sometimes called the crossed-extension reflex, and it is enacted for postural support. If, for example, you are withdrawing your foot from a painful stimulus, the other leg needs to be prepared to hold your weight.[9]

Related Testing

The withdrawal reflex can be tested using an electromyogram (EMG). This device measures the electrical activity of peripheral nerves and striated skeletal muscles and includes a needle EMG and nerve conduction studies (NCS). The EMG was first described in 1943 by Weddell et al., who pioneered its use in examining muscles.[10] 

Nerve conduction studies provide an efficient method of quantifying the conduction velocity (CV) of nerves and the amplitude of sensory nerve action potentials (SNAPs) and compound motor action potentials (cMAPs). The nerve CV reflects the speed of propagation of action potentials (APs) by saltatory conduction along myelinated axons in a peripheral nerve. SNAP amplitude is determined by the number of axons in a sensory nerve, while the amplitude of cMAPs reflects an integrated function of the motor axons, neuromuscular junction (NMJ), and striated muscle. Needle EMGs are utilized to detect myopathic changes in muscle in response to denervation. Very fine needles are inserted into several muscles, each with a microscopic electrode that can pick up muscles' normal and abnormal electrical signals.

In most cases, an experienced clinician will perform both elements of an EMG, but in certain situations, only one may be performed. Utilizing both of these procedures helps establish if damage occurred in the motor and/or sensory nerve cell bodies or within the peripheral nerves and can also determine if an issue is related to the axon or the myelin sheath (i.e., axonal vs. demyelinating neuropathies). Nerve damage may be focal, multifocal, or generalized, with focal nerve damage typically due to compression of a nerve at an entrapment site, as may occur at the carpal, cubital, or tarsal tunnel, radial groove, Guyon's canal, or fibular head.[11] 

Clinical Significance

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[12]. 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. Genetic variances can alter an individual's perception of pain by modifying the sodium ion channels in sensory neurons.[13] 

The withdrawal reflex may also be impacted if motor neurons or their synapses with musculature are damaged, as can be seen in amyotrophic lateral sclerosis (ALS).[14] Autoimmune diseases such as myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) negatively impact the communication between lower motor neurons and the muscles they act upon, which theoretically can alter the withdrawal reflex.[15] A loss of the withdrawal reflex can also be seen in transverse myelitis, a demyelinating condition of the spinal cord with multiple causes, including multiple sclerosis, fungal infections (Mycoplasma pneumoniae), and viruses (CMV, HSV, and enterovirus). Patients with transverse myelitis will experience motor weakness, autonomic nervous system (ANS) and sensory dysfunction, and diminished reflexes.[16] Overriding of the withdrawal reflex can be seen in drugged, drunk, or unconscious patients. These patients will not exhibit this reflex. 

Specific modulators of the withdrawal reflex have long been topics of research, which has revealed that the reflex pattern may undergo modulation by running, different phases of walking, stimulus intensity, and even the load on the leg. In fact, the particular phase of walking has 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.[17] Non-invasive vagal nerve stimulation has also been found to increase the threshold of the withdrawal reflex to a single stimulus.[18] Stroke is the fifth leading cause of morbidity and mortality in the United States, with stroke patients frequently exhibiting 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 by reducing spasticity, suggesting that this may be a valuable tool in treating post-stroke spasticity.[19]

Premature infants may display a flexion withdrawal reflex as early as 22 weeks and three days gestational age. Compared to full-term newborns, the flexion withdrawal reflex of premature infants has a very low threshold throughout the first three days of life and continuously increases up to a corrected age of 37–40 gestational weeks, which reflects the changing spinal cord excitability in human development.[20]