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Control of the Cutaneous Circulation by the Central Nervous System

William Blessing, Robin McAllen, Michael McKinley

10.1002/cphy.c150034

Source: Volume 6, Issue 3, July 2016

Published online: June 2016

Full Article on Wiley Online Library



ABSTRACT

The central nervous system (CNS), via its control of sympathetic outflow, regulates blood flow to the acral cutaneous beds (containing arteriovenous anastomoses) as part of the homeostatic thermoregulatory process, as part of the febrile response, and as part of cognitive‐emotional processes associated with purposeful interactions with the external environment, including those initiated by salient or threatening events (we go pale with fright). Inputs to the CNS for the thermoregulatory process include cutaneous sensory neurons, and neurons in the preoptic area sensitive to the temperature of the blood in the internal carotid artery. Inputs for cognitive‐emotional control from the exteroceptive sense organs (touch, vision, sound, smell, etc.) are integrated in forebrain centers including the amygdala. Psychoactive drugs have major effects on the acral cutaneous circulation. Interoceptors, chemoreceptors more than baroreceptors, also influence cutaneous sympathetic outflow. A major advance has been the discovery of a lower brainstem control center in the rostral medullary raphé, regulating outflow to both brown adipose tissue (BAT) and to the acral cutaneous beds. Neurons in the medullary raphé, via their descending axonal projections, increase the discharge of spinal sympathetic preganglionic neurons controlling the cutaneous vasculature, utilizing glutamate, and serotonin as neurotransmitters. Present evidence suggests that both thermoregulatory and cognitive‐emotional control of the cutaneous beds from preoptic, hypothalamic, and forebrain centers is channeled via the medullary raphé. Future studies will no doubt further unravel the details of neurotransmitter pathways connecting these rostral control centers with the medullary raphé, and those operative within the raphé itself. © 2016 American Physiological Society. Compr Physiol 6:1161‐1197, 2016.

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Figure 1. Figure 1. Infrared images of the human hand before and after oral administration of clozapine, a second‐generation antipsychotic drug that acts within the CNS to inhibit sympathetic outflow to the acral cutaneous vasculature. Modified from (21).
Figure 2. Figure 2. Diagram of inferred inputs to spinal preganglionic CVC neurons, based on the formulation of Jänig (135) and modified to emphasize the role of the medullary regulatory nuclei (see later in this review).
Figure 3. Figure 3. (A) Contrasting effects on body temperature elicited by systemic activation of subclasses of serotonin (5‐HT) receptors (modified from (110). (B) Effects of systemic activation of 5‐HT2A receptors by DOI on tail artery blood flow and BAT and body temperature in rat. SR 46349B (5‐HT2A) antagonist reverses the effects. (C) Effects of systemic activation of 5‐HT2A receptors by DOI on ear pinna and mesenteric blood flow, and body temperature in rabbit. B and C modified from (34).
Figure 4. Figure 4. (A, B) Simultaneous recording of sympathetic discharge to the tail and to the kidney in the anesthetized rat. Excitation of neuronal discharge with focal intramedullary injection of L‐glutamate (see raphé injection site in B) selectively activates tail artery sympathetic discharge. (C‐E) Recording of ear pinna blood flow and arterial blood pressure in the anesthetized rabbit. Electrical stimulation of the raphé markedly reduces ear pinna blood flow with minimal effects on arterial blood pressure. Inhibiting raphé neurons with focal injections of GABA markedly increases ear pinna blood flow, again with minimal effects on arterial pressure. Modified from (271) and (36).
Figure 5. Figure 5. Effect of trunkal cooling on ear pinna (A, rabbit) and tail (B, rat) cutaneous sympathetic nerve discharge before and after inhibition of neuronal discharge in the medullary raphé. Modified from (245).
Figure 6. Figure 6. Distribution of VGLUT3 immunoreactive neurons (open red circles) and pseudorabies virus (PRV) immunoreactive neurons (open black circles) and doubly‐labeled neurons (filled red circles) in the ventral medulla oblongata 171 hours after injection of virus into rat tail. cRPa, caudal raphe pallidus; PPy, parapyramidal region; Py, pyramidal tract; rMg, raphe magnus; rOB, raphe obscurus; rRPa, rostral raphe pallidus. Modified from (223).
Figure 7. Figure 7. Recording of ear pinna sympathetic nerve discharge, skin temperature, body temperature and arterial pressure in an anesthetized rabbit. The circled numbers (1‐6) in the top panel correspond to the time indicated by the circled numbers on the x axis. 8‐OH‐DPAT was administered systemically, and WAY‐100635 was microinjected into the raphé at the indicated times. The 10‐min time base bar applies to the bottom three panels. Modified from (240).
Figure 8. Figure 8. Simultaneously recorded rat BAT and tail cutaneous sympathetic discharge (anesthetized animal) in response to repeated changes in skin temperature and a gradual fall in core (rectal) temperature. Tail sympathetic discharge is initially more responsive to the change in skin temperature, but as core temperature falls, the increase in tail sympathetic discharge is sustained even when skin temperature is increased. BAT sympathetic discharge increases with the fall in core temperature, but it remains responsive to changes in skin temperature even when core temperature is very low. Modified from (250).
Figure 9. Figure 9. Electrical activity of raphé‐projecting preoptic neurons that respond to skin warming with increased activity (A and C) or to repeated episodes of skin cooling with increases in activity (B and D). They were also influenced by core temperature, (C and D) as indicated during periods of rewarming indicated by the gray bars. From (308).
Figure 10. Figure 10. Diagram of proposed thermoregulatory neural pathways from the preoptic area to medullary raphé controlling cutaneous blood flow in the rat tail. Taken from (308).
Figure 11. Figure 11. The cutaneous sympathetic nerve activity to back skin responds to a preoptic injection of PGE2 (30 ng) as well as to skin cooling. However, the response is less than the simultaneous changes in activity of tail sympathetic nerve activity. Taken from (311).
Figure 12. Figure 12. (A) Inhibition of the medullary raphé caused by microinjection of GABA therein (at arrowheads) reduces the effect of intracerebroventricular injection of PGE1 (at broken vertical line at right‐hand side) as well as the effect of cooling (during control period) on tail sympathetic cutaneous nerve activity (SNA) (top trace). Splanchnic SNA, heart rate, and arterial pressure are also shown. Modified from (164). (B) Injection of muscimol into the rostral medial preoptic region (RMPO) reduces tail SNA that follows the microinjection of PGE2 into the RMPO. (B) By contrast, similar injection of muscimol into RMPO of rats not treated with PGE2 increased tail SNA. Modified from (309).
Figure 13. Figure 13. Diagram of proposed neural pathways whereby PGE2 in the rostral medial preoptic region causes increases sympathetic nerve activity and vasoconstriction in rat tail blood vessels. Taken from (309).
Figure 14. Figure 14. (A) Acute decrease in human finger volume in response to a sudden shout. Modified from (303). (B) Scattergrams comparing simultaneously measured pulsation amplitudes in pairs of distal cutaneous beds. The highly significant correlation between pairs is abolished by prior interruption of the sympathetic supply to one member of the pair. Modified from (52).
Figure 15. Figure 15. Effect of a psychological stressor on hand skin temperature measured with infrared thermography. The shower murder scene of Alfred Hitchock's movie “Psycho” was presented to volunteers. The infrared thermograph of the viewer's hand at the time when Marion was killed in the shower was subtracted from the thermograph taken before the murderer entered the bathroom. The temperature of the dorsal fingertips decreased by more than 2C°. Modified from (155).
Figure 16. Figure 16. Integrated peroneal nerve cutaneous sympathetic nerve discharge (middle trace), respiratory movements (upper trace), and intra‐arterial blood pressure in a human subject asked to solve an arithmetic problem (mental stress arrows). Modified from (318). Originally published in (80).
Figure 17. Figure 17. (A) Blood flow signals in a conscious rabbit resting in a small cage in the laboratory, recorded simultaneously from Doppler ultrasonic probes chronically implanted around different arteries. Modified from (339). (B) Blood flow signals in a conscious rabbit recorded simultaneously from Doppler ultrasonic probes chronically implanted around left and right ear pinna arteries (Blessing, unpublished). (C, D) Blood flow signal recorded from a Doppler ultrasonic probe chronically implanted around the base of the tail artery in a rat. The artery constricts in response to an unexpected sound, as shown on the expanded time scale in D. (Blessing, unpublished).
Figure 18. Figure 18. (A) Hippocampal EEG recorded from a chronically implanted monopolar electrode (upper trace) and Doppler flow signal recorded from a probe chronically implanted around the ear pinna artery (lower trace) in a conscious rabbit resting in a small cage. A sudden whistle is sounded at the indicated time. (B) Blood flow signals in a conscious rabbit recorded simultaneously from Doppler ultrasonic probes chronically implanted around left and right ear pinna arteries, approximately one week after section of the right cervical sympathetic trunk (CST). Modified from (339) and (34).
Figure 19. Figure 19. Infrared images of a rat receiving electric shocks after transfer to a shock box in which he previously received electric shocks and after transfer back to the home box (upper panels) and similar images of a rat previously transferred to the shock box without receiving shocks (lower panels). The color‐coded temperature scale (°C) is shown on the right hand side of the Figure. Taken from (328).
Figure 20. Figure 20. Changes in skin and brain temperature in a pigtail monkey in response to changes in lighting. Ambient temperature 25°C. Top trace shows “ON” and “OFF” times of the light in the recording chamber. Taken from (10).
Figure 21. Figure 21. (A) Simultaneously recorded BAT, brain and body temperature, food intake, behavioral activity, and tail artery blood flow in an individual rat during both light and dark periods. The transient large amplitude changes in the weight of the food container indicate mechanical disturbances. Ambient temperature 25°C. (B) Group results showing timing of tail artery blood flow, behavioral activity, BAT and body temperature, and arterial blood pressure in relation to onset of eating during active phases from the 12‐h dark period in rats. Modified from (23).
Figure 22. Figure 22. Mean ± SEM (5 min bins) proximal and distal skin temperature, and core body temperature in male humans during a control constant routine period and after the “lights off” signal to sleep. Mean sleep onset latency was 12 ± 4 min. The shaded vertical bars indicate periods of REM sleep. Modified from (168).
Figure 23. Figure 23. Changes in finger temperature (30 s bins) after the “lights off” signal to sleep for the different circadian phases during a 45‐h trial period. Modified from (174).
Figure 24. Figure 24. Change in body and tail temperatures after intraperitoneal administration of saline (broken arrow) or amphetamine (unbroken arrow at time zero) at the doses indicated. Modified from (42).
Figure 25. Figure 25. Effect of chlorpromazine on tail artery blood flow in the conscious unrestrained rat. The drug substantially reduces the sudden falls in flow normally elicited by an alerting stimulus. Blessing (unpublished). See quantitative results in (32).
Figure 26. Figure 26. (A) Core body temperature and ear pinna blood flow in a conscious rabbit transferred from ambient temperature to a 10°C environment and the effect of intravenously administered clozapine. (B) Core body temperature and ear pinna blood flow in a conscious rabbit treated with intravenous lipopolysaccharide (LPS) and then with intravenous olanzapine. Modified from (26).
Figure 27. Figure 27. Infrared images showing the effect of MDMA on ear pinna blood flow in rabbits, and the reversal of the vasoconstriction by clozapine. Blessing (unpublished). For quantitative data, see (35).
Figure 28. Figure 28. Effects of acute muscimol injection (A) or chronic ibotenic acid (B) bilateral intra‐amygdala injections on tail artery blood flow in the rat. Modified from (208).


Figure 1. Infrared images of the human hand before and after oral administration of clozapine, a second‐generation antipsychotic drug that acts within the CNS to inhibit sympathetic outflow to the acral cutaneous vasculature. Modified from (21).


Figure 2. Diagram of inferred inputs to spinal preganglionic CVC neurons, based on the formulation of Jänig (135) and modified to emphasize the role of the medullary regulatory nuclei (see later in this review).


Figure 3. (A) Contrasting effects on body temperature elicited by systemic activation of subclasses of serotonin (5‐HT) receptors (modified from (110). (B) Effects of systemic activation of 5‐HT2A receptors by DOI on tail artery blood flow and BAT and body temperature in rat. SR 46349B (5‐HT2A) antagonist reverses the effects. (C) Effects of systemic activation of 5‐HT2A receptors by DOI on ear pinna and mesenteric blood flow, and body temperature in rabbit. B and C modified from (34).


Figure 4. (A, B) Simultaneous recording of sympathetic discharge to the tail and to the kidney in the anesthetized rat. Excitation of neuronal discharge with focal intramedullary injection of L‐glutamate (see raphé injection site in B) selectively activates tail artery sympathetic discharge. (C‐E) Recording of ear pinna blood flow and arterial blood pressure in the anesthetized rabbit. Electrical stimulation of the raphé markedly reduces ear pinna blood flow with minimal effects on arterial blood pressure. Inhibiting raphé neurons with focal injections of GABA markedly increases ear pinna blood flow, again with minimal effects on arterial pressure. Modified from (271) and (36).


Figure 5. Effect of trunkal cooling on ear pinna (A, rabbit) and tail (B, rat) cutaneous sympathetic nerve discharge before and after inhibition of neuronal discharge in the medullary raphé. Modified from (245).


Figure 6. Distribution of VGLUT3 immunoreactive neurons (open red circles) and pseudorabies virus (PRV) immunoreactive neurons (open black circles) and doubly‐labeled neurons (filled red circles) in the ventral medulla oblongata 171 hours after injection of virus into rat tail. cRPa, caudal raphe pallidus; PPy, parapyramidal region; Py, pyramidal tract; rMg, raphe magnus; rOB, raphe obscurus; rRPa, rostral raphe pallidus. Modified from (223).


Figure 7. Recording of ear pinna sympathetic nerve discharge, skin temperature, body temperature and arterial pressure in an anesthetized rabbit. The circled numbers (1‐6) in the top panel correspond to the time indicated by the circled numbers on the x axis. 8‐OH‐DPAT was administered systemically, and WAY‐100635 was microinjected into the raphé at the indicated times. The 10‐min time base bar applies to the bottom three panels. Modified from (240).


Figure 8. Simultaneously recorded rat BAT and tail cutaneous sympathetic discharge (anesthetized animal) in response to repeated changes in skin temperature and a gradual fall in core (rectal) temperature. Tail sympathetic discharge is initially more responsive to the change in skin temperature, but as core temperature falls, the increase in tail sympathetic discharge is sustained even when skin temperature is increased. BAT sympathetic discharge increases with the fall in core temperature, but it remains responsive to changes in skin temperature even when core temperature is very low. Modified from (250).


Figure 9. Electrical activity of raphé‐projecting preoptic neurons that respond to skin warming with increased activity (A and C) or to repeated episodes of skin cooling with increases in activity (B and D). They were also influenced by core temperature, (C and D) as indicated during periods of rewarming indicated by the gray bars. From (308).


Figure 10. Diagram of proposed thermoregulatory neural pathways from the preoptic area to medullary raphé controlling cutaneous blood flow in the rat tail. Taken from (308).


Figure 11. The cutaneous sympathetic nerve activity to back skin responds to a preoptic injection of PGE2 (30 ng) as well as to skin cooling. However, the response is less than the simultaneous changes in activity of tail sympathetic nerve activity. Taken from (311).


Figure 12. (A) Inhibition of the medullary raphé caused by microinjection of GABA therein (at arrowheads) reduces the effect of intracerebroventricular injection of PGE1 (at broken vertical line at right‐hand side) as well as the effect of cooling (during control period) on tail sympathetic cutaneous nerve activity (SNA) (top trace). Splanchnic SNA, heart rate, and arterial pressure are also shown. Modified from (164). (B) Injection of muscimol into the rostral medial preoptic region (RMPO) reduces tail SNA that follows the microinjection of PGE2 into the RMPO. (B) By contrast, similar injection of muscimol into RMPO of rats not treated with PGE2 increased tail SNA. Modified from (309).


Figure 13. Diagram of proposed neural pathways whereby PGE2 in the rostral medial preoptic region causes increases sympathetic nerve activity and vasoconstriction in rat tail blood vessels. Taken from (309).


Figure 14. (A) Acute decrease in human finger volume in response to a sudden shout. Modified from (303). (B) Scattergrams comparing simultaneously measured pulsation amplitudes in pairs of distal cutaneous beds. The highly significant correlation between pairs is abolished by prior interruption of the sympathetic supply to one member of the pair. Modified from (52).


Figure 15. Effect of a psychological stressor on hand skin temperature measured with infrared thermography. The shower murder scene of Alfred Hitchock's movie “Psycho” was presented to volunteers. The infrared thermograph of the viewer's hand at the time when Marion was killed in the shower was subtracted from the thermograph taken before the murderer entered the bathroom. The temperature of the dorsal fingertips decreased by more than 2C°. Modified from (155).


Figure 16. Integrated peroneal nerve cutaneous sympathetic nerve discharge (middle trace), respiratory movements (upper trace), and intra‐arterial blood pressure in a human subject asked to solve an arithmetic problem (mental stress arrows). Modified from (318). Originally published in (80).


Figure 17. (A) Blood flow signals in a conscious rabbit resting in a small cage in the laboratory, recorded simultaneously from Doppler ultrasonic probes chronically implanted around different arteries. Modified from (339). (B) Blood flow signals in a conscious rabbit recorded simultaneously from Doppler ultrasonic probes chronically implanted around left and right ear pinna arteries (Blessing, unpublished). (C, D) Blood flow signal recorded from a Doppler ultrasonic probe chronically implanted around the base of the tail artery in a rat. The artery constricts in response to an unexpected sound, as shown on the expanded time scale in D. (Blessing, unpublished).


Figure 18. (A) Hippocampal EEG recorded from a chronically implanted monopolar electrode (upper trace) and Doppler flow signal recorded from a probe chronically implanted around the ear pinna artery (lower trace) in a conscious rabbit resting in a small cage. A sudden whistle is sounded at the indicated time. (B) Blood flow signals in a conscious rabbit recorded simultaneously from Doppler ultrasonic probes chronically implanted around left and right ear pinna arteries, approximately one week after section of the right cervical sympathetic trunk (CST). Modified from (339) and (34).


Figure 19. Infrared images of a rat receiving electric shocks after transfer to a shock box in which he previously received electric shocks and after transfer back to the home box (upper panels) and similar images of a rat previously transferred to the shock box without receiving shocks (lower panels). The color‐coded temperature scale (°C) is shown on the right hand side of the Figure. Taken from (328).


Figure 20. Changes in skin and brain temperature in a pigtail monkey in response to changes in lighting. Ambient temperature 25°C. Top trace shows “ON” and “OFF” times of the light in the recording chamber. Taken from (10).


Figure 21. (A) Simultaneously recorded BAT, brain and body temperature, food intake, behavioral activity, and tail artery blood flow in an individual rat during both light and dark periods. The transient large amplitude changes in the weight of the food container indicate mechanical disturbances. Ambient temperature 25°C. (B) Group results showing timing of tail artery blood flow, behavioral activity, BAT and body temperature, and arterial blood pressure in relation to onset of eating during active phases from the 12‐h dark period in rats. Modified from (23).


Figure 22. Mean ± SEM (5 min bins) proximal and distal skin temperature, and core body temperature in male humans during a control constant routine period and after the “lights off” signal to sleep. Mean sleep onset latency was 12 ± 4 min. The shaded vertical bars indicate periods of REM sleep. Modified from (168).


Figure 23. Changes in finger temperature (30 s bins) after the “lights off” signal to sleep for the different circadian phases during a 45‐h trial period. Modified from (174).


Figure 24. Change in body and tail temperatures after intraperitoneal administration of saline (broken arrow) or amphetamine (unbroken arrow at time zero) at the doses indicated. Modified from (42).


Figure 25. Effect of chlorpromazine on tail artery blood flow in the conscious unrestrained rat. The drug substantially reduces the sudden falls in flow normally elicited by an alerting stimulus. Blessing (unpublished). See quantitative results in (32).


Figure 26. (A) Core body temperature and ear pinna blood flow in a conscious rabbit transferred from ambient temperature to a 10°C environment and the effect of intravenously administered clozapine. (B) Core body temperature and ear pinna blood flow in a conscious rabbit treated with intravenous lipopolysaccharide (LPS) and then with intravenous olanzapine. Modified from (26).


Figure 27. Infrared images showing the effect of MDMA on ear pinna blood flow in rabbits, and the reversal of the vasoconstriction by clozapine. Blessing (unpublished). For quantitative data, see (35).


Figure 28. Effects of acute muscimol injection (A) or chronic ibotenic acid (B) bilateral intra‐amygdala injections on tail artery blood flow in the rat. Modified from (208).
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Article Title: Control of the Cutaneous Circulation by the Central Nervous System
 

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William Blessing, Robin McAllen, Michael McKinley. Control of the Cutaneous Circulation by the Central Nervous System. Compr Physiol 2016, 6: 1161-1197. doi: 10.1002/cphy.c150034