Sweat Gland Innervation

Introduction: Function & Structure of Sweat Glands

• Sweating is an effective physiologic thermal defense mechanism for dissipating heat when core temperature exceeds that of ambient temperature. This is highly useful during pathological events (e.g., heat injury, endocrine abnormalities, medication side effects) as well as in nonpathological states, such as exercise.
• Please see the OA summary “Normal Thermoregulation” section for more details. Link
• Sweat is also secreted in a nonthermoregulatory capacity, as seen during emotional stress.
• In addition to heat dissipation, it is theorized that sweat glands serve an excretory function, like the renal system. However, the function of sweat glands as an excretory organ is unclear and likely insignificant.¹
• There are three types of sweat glands (eccrine, apocrine, and apoecrine), which differ in distribution, sweat gland density, and sweat volume. Eccrine sweat glands are the most numerous, totaling approximately 2–4 million and comprising 90% of the total number of sweat glands. These glands are the primary effectors of thermoregulation, covering a large surface area on the face, limbs, and trunk. Additionally, they can be found on both hairy and nonhairy skin.^1,2
• The content of sweat varies by body region and, accordingly, by the producing sweat gland. The primary solutes composing sweat are sodium and chloride. Other electrolytes and ions in far less quantities include potassium, calcium, magnesium, iron, zinc, and copper.1 Sweat also has been reported to contain trace amounts of other molecules, such as urea, ammonia, lactate, free fatty acids, proteins, peptides, and toxins.²
• Sweat rate can be modulated by biological, physiologic, and environmental factors. For example, heat acclimatization, aerobic training, and male gender are associated with higher whole-body sweat rates, whereas dehydration and aging impair the sweat response.¹

Sweat Gland Innervation

• Sweat gland activation is under the control of the SNS and involves either the hypothalamus or the limbic system. There are three neurotransmitters involved with regulating sweat gland secretion: acetylcholine, norepinephrine (NE), and epinephrine (EP).^1,2
  • The main thermoregulatory function of sweat glands is mediated by the hypothalamus centrally and ACh terminally (see below), while the emotional response of sweating is mediated by the limbic system centrally and catecholamines terminally.
• Centrally, the preoptic area of the hypothalamus is responsible for setting the body’s temperature set point and integrating afferent input from central and peripheral thermoreceptors. When the physiologic temperature exceeds the set point, the hypothalamus signals the spinal cord via descending pathways to initiate sweating.⁴
• Thermoregulatory sweating is under the control of the ANS. Sweat glands are one of several organs within the body that do not exhibit reciprocal innervation of both the SNS and parasympathetic nervous systems. Specifically, sweat gland innervation is solely mediated by the sympathetic branch of the ANS.^1-4
• The organization and physiology of the sweat gland nerve impulse and conduction share both similarities and differences with those of other effector organs of the SNS (Table 1). For example, both sweat glands and other effectors of the SNS (i.e., smooth muscle, glands, cardiac muscle) begin with a short preganglionic axon originating from the thoracolumbar region (T1-L3), which synapses with a nicotinic receptor in an autonomic ganglion before becoming a longer postganglionic fiber.^1-4
• However, key differences between sweat glands and other effector organs of the SNS are evident in the receptors and neurotransmitters released at the effector organ. Postganglionic neurons of the SNS are all NE-releasing adrenergic neurons, except those synapsing onto cholinergic sweat glands, which release ACh. Specifically, ACh is released from postganglionic neurons onto muscarinic subtype 3 (M₃) receptors on sweat glands. At the same time, NE is the terminal neurotransmitter released onto both alpha (⍺) and beta (β) receptors for all other SNS effector organs.^1-4

• Following descending input from the hypothalamic thermoregulatory center, autonomic activation of sweat glands begins within T1-L3 of the spinal cord (Figure 1).^1-3
  • Preganglionic sympathetic neurons of sweat glands originate within nuclei of the T1-L3 region of the spinal cord.
  • These preganglionic axons leave the spinal cord via the ventral motor roots and synapse onto the of the sympathetic chain, which lie adjacent to the spinal cord.
  • These synapses may occur along ganglia at the same segmental chain level of the sympathetic chain or at multiple levels, either in the cranial or caudal directions, along the sympathetic chain.
  • Regardless of the segmental level of the spinal cord at which the synapse occurs within the sympathetic chain, there is release of ACh from the terminal preganglionic nerve fiber ending, which synapses onto a nicotinic receptor on a postganglionic fiber.
  • Once activated, the postganglionic fibers originating from the sympathetic chain travel to the periphery and innervate muscarinic receptor type III (M₃) on sweat glands distributed throughout the body.

• The postganglionic nicotinic receptor of sweat glands is similar to those at motor end plates and in ganglia of other effector organs throughout the body. Specifically, it comprises five subunits: two α, one β, one δ, and one γ. When an ACh molecule binds to both α subunits, the channel undergoes a conformational change, allowing sodium and potassium to flow down their respective electrochemical gradients towards a depolarized state.³
• Sweat gland M₃ receptors are G-protein coupled receptors (G_q) which, upon binding of ACh, cause 1) release of the ⍺_q subunit of the G_q protein, and 2) release and replacement of GDP from the ⍺_q subunit with a GTP molecule. The GTP-⍺_q subunit complex leads to activation of Phospholipase C and generation of inositol triphosphate (IP₃) and diacylglycerol. The generated IP₃ subsequently releases stored calcium, which, together with diacylglycerol, activates protein kinase C and phosphorylates proteins, allowing for final physiological actions (Figure 2).³

• Sweating also occurs in a nonthermoregulatory capacity, which is mediated by the catecholamines NE and EP. Emotional changes regulated within the limbic system travel via efferent fibers and synapse onto preganglionic fibers located in the nucleus intermediolateralis the ventral horn of the spinal cord. Once activated, these preganglionic fibers synapse onto the adrenal medulla, releasing ACh onto nicotinic receptors. The catecholamines NE and EP are subsequently released and travel to the sweat glands to for humoral activation.^1,2
• The humoral role of catecholamines in sweat gland activation under times of emotional stress is confirmed by the fact that no NE-secreting postganglionic nerve fibers have been found near sweat glands.²
• Once innervated by M₃ receptor activation, sweat glands secrete hypotonic sweat onto the skin through a coordinated mechanism involving ion secretion, reabsorption, channel proteins, active transport, and passive transport.¹