Peripheral thermoreceptors in innocuous temperature detection.

The mammalian skin is innervated by cold-sensitive afferent neurons. These neurons exhibit ongoing activity at temperatures between ~10 and 42°C, are activated by innocuous cold stimuli, inhibited by warm stimuli and are mechanoinsensitive. Their axons are small-diameter myelinated (Aδ-) fibers in primates and unmyelinated (C-) fibers in nonprimate mammals. The mammalian skin is innervated by warm-sensitive afferent neurons. The density of innervation by these neurons is lower than that by cold-sensitive afferents. They exhibit ongoing activity between ~38 and 48°C, are activated by warm stimuli, inhibited by cold stimuli, and are mechanoinsensitive. Their axons are unmyelinated (C-) fibers. Cold-sensitive unmyelinated afferent neurons exhibit prominent cold sensitivity of their axons (in rats). The discharge pattern of the cutaneous cold-sensitive afferent neurons is fully preserved after nerve injury. Ongoing impulse activity and cold-evoked impulses originate ectopically at the nerve injury site. Deep somatic tissues and viscera are innervated by thermosensitive afferent neurons. Most are warm-sensitive and mechanoinsensitive and have unmyelinated axons. These afferent neurons have only rarely and incompletely been studied, e.g., in the upper gastrointestinal tract, the liver (both vagal afferents), the dorsal abdominal wall, and the skeletal muscle. Spinal cord warm sensitivity may be mediated by cutaneous afferent neurons with unmyelinated axons that are excited by spinal cord warming.

Mechano- and thermosensitivity of injured muscle afferents 20 to 80 days after nerve injury.

Chronic injury of limb nerves leading to neuropathic pain affects deep somatic nerves. Here the functional properties of injured afferent fibers in the lateral gastrocnemius-soleus nerve were investigated 20 and 80 days after suturing the central stump of this muscle nerve to the distal stump of the sural nerve in anesthetized rats. Neurophysiological recordings were made from afferent axons identified in either the sciatic nerve (87 A-, 63 C-fibers) or the dorsal root L4/L5 (52 A-, 26 C-fibers) by electrical stimulation of the injured nerve. About 70% of the functionally identified A-fibers had regenerated into skin by 80 days after nerve suture; the remaining A-fibers could be activated only from the injured nerve. In contrast, 93% of the functionally identified C-fibers could only be activated from the injured sural nerve after 80 days. Nearly half of the injured A- (45%) and C-fibers (44%) exhibited ongoing and/or mechanically or thermally evoked activity. Because ~50% of the A- and C-fibers are somatomotor or sympathetic postganglionic axons, respectively, probably all injured muscle afferent A- and C-fibers developed ectopic activity. Ongoing activity was present in 17% of the A- and 46% of the C-fibers. Mechanosensitivity was present in most injured A- (99%) and C-fibers (85%), whereas thermosensitivity was more common in C-fibers (cold 46%, heat 47%) than in A-fibers (cold 18%, heat 12%). Practically all thermosensitive A-fibers and C-fibers were also mechanosensitive. Thus, unlike cutaneous axons, almost all A- and C-fibers afferents in injured muscle nerves demonstrate ectopic activity, even chronically after nerve injury. NEW & NOTEWORTHY After chronic injury of a muscle nerve, allowing the nerve fibers to regenerate to the target tissue, 1) most afferent A-fibers are mechanosensitive and regenerate to the target tissue; 2) ectopic ongoing activity, cold sensitivity, and heat sensitivity significantly decrease with time after injury in A-afferents; 3) most afferent C-fibers do not regenerate to the target tissue; and 4) injured C-afferents maintain the patterns of ectopic discharge properties they already show soon after nerve injury.

The Sacral Autonomic Outflow Is Spinal, but Not "Sympathetic".

A recent article published in a high-profile journal proposed to reclassify the sacral autonomic outflow as being part of the sympathetic system. In this commentary, arguments against this erroneous proposal are provided. Anat Rec, 300:1369-1370, 2017. © 2017 Wiley Periodicals, Inc.

Acute inflammation in the joint: its control by the sympathetic nervous system and by neuroendocrine systems.

Inflammation of tissues is under neural control involving neuroendocrine, sympathetic and central nervous systems. Here we used the acute experimental inflammatory model of bradykinin-induced plasma extravasation (BK-induced PE) of the rat knee joint to investigate the neural and neuroendocrine components controlling this inflammation. 1. BK-induced PE is largely dependent on the sympathetic innervation of the synovium, but not on activity in these neurons and not on release of norepinephrine. 2. BK-induced PE is under the control of the hypothalamo-pituitary-adrenal (HPA) system and the sympatho-adrenal (SA) system, activation of both leading to depression of BK-induced PE. The inhibitory effect of the HPA system is mediated by corticosterone and dependent on the sympathetic innervation of the synovium. The inhibitory effect of the SA system is mediated by epinephrine and ß2-adrenoceptors. 3. BK-induced PE is inhibited during noxious stimulation of somatic or visceral tissues and is mediated by the neuroendocrine systems. The nociceptive-neuroendocrine reflex circuits are (for the SA system) spinal and spino-bulbo-spinal. 4. The nociceptive-neuroendocrine reflex circuits controlling BK-induced PE are under powerful inhibitory control of vagal afferent neurons innervating the defense line (connected to the gut-associated lymphoid tissue) of the gastrointestinal tract. This inhibitory link between the visceral defense line and the central mechanisms controlling inflammatory mechanisms in body tissues serves to co-ordinate protective defensive mechanisms of the body. 5. The circuits of the nociceptive-neuroendocrine reflexes are under control of the forebrain. In this way, the defensive mechanisms of inflammation in the body are co-ordinated, optimized, terminated as appropriate, and adapted to the behavior of the organism.

Sympathetic nervous system and inflammation: a conceptual view.

The peripheral sympathetic nervous system is organized into function-specific pathways that transmit the activity from the central nervous system to its target tissues. The transmission of the impulse activity in the sympathetic ganglia and to the effector tissues is target cell specific and guarantees that the centrally generated command is faithfully transmitted. This is the neurobiological basis of autonomic regulations in which the sympathetic nervous system is involved. Each sympathetic pathway is connected to distinct central circuits in the spinal cord, lower and upper brain stem and hypothalamus. In addition to its conventional functions, the sympathetic nervous system is involved in protection of body tissues against challenges arising from the environment as well as from within the body. This function includes the modulation of inflammation, nociceptors and above all the immune system. Primary and secondary lymphoid organs are innervated by sympathetic postganglionic neurons and processes in the immune tissue are modulated by activity in these sympathetic neurons via adrenoceptors in the membranes of the immune cells (see Bellinger and Lorton, 2014). Are the primary and secondary lymphoid organs innervated by a functionally specific sympathetic pathway that is responsible for the modulation of the functioning of the immune tissue by the brain? Or is this modulation of immune functions a general function of the sympathetic nervous system independent of its specific functions? Which central circuits are involved in the neural regulation of the immune system in the context of neural regulation of body protection? What is the function of the sympatho-adrenal system, involving epinephrine, in the modulation of immune functions?

Reflex inhibition of cutaneous and muscle vasoconstrictor neurons during stimulation of cutaneous and muscle nociceptors.

Cutaneous (CVC) and muscle (MVC) vasoconstrictor neurons exhibit typical reflex patterns to physiological stimulation of somatic and visceral afferent neurons. Here we tested the hypothesis that CVC neurons are inhibited by stimulation of cutaneous nociceptors but not of muscle nociceptors and that MVC neurons are inhibited by stimulation of muscle nociceptors but not of cutaneous nociceptors. Activity in the vasoconstrictor neurons was recorded from postganglionic axons isolated from the sural nerve or the lateral gastrocnemius-soleus nerve in anesthetized rats. The nociceptive afferents were excited by mechanical stimulation of the toes of the ipsilateral hindpaw (skin), by hypertonic saline injected into the ipsi- or contralateral gastrocnemius-soleus muscle, or by heat or noxious cold stimuli applied to the axons in the common peroneal nerve or tibial nerve. The results show that CVC neurons are inhibited by noxious stimulation of skin but not by noxious stimulation of skeletal muscle and that MVC neurons are inhibited by noxious stimulation of skeletal muscle but not by noxious stimulation of skin. These inhibitory reflexes are mostly lateralized and are most likely organized in the spinal cord. Stimulation of nociceptive cold-sensitive afferents does not elicit inhibitory or excitatory reflexes in CVC or MVC neurons. The reflex inhibition of activity in CVC or MVC neurons generated by stimulation of nociceptive cutaneous or muscle afferents during tissue injury leads to local increase of blood flow, resulting in an increase of transport of immunocompetent cells, proteins, and oxygen to the site of injury and enhancing the processes of healing.

Responses of intact and injured sural nerve fibers to cooling and menthol.

Intact and injured cutaneous C-fibers in the rat sural nerve are cold sensitive, heat sensitive, and/or mechanosensitive. Cold-sensitive fibers are either low-threshold type 1 cold sensitive or high-threshold type 2 cold sensitive. The hypothesis was tested, in intact and injured afferent nerve fibers, that low-threshold cold-sensitive afferent nerve fibers are activated by the transient receptor potential melastatin 8 (TRPM8) agonist menthol, whereas high-threshold cold-sensitive C-fibers and cold-insensitive afferent nerve fibers are menthol insensitive. In anesthetized rats, activity was recorded from afferent nerve fibers in strands isolated from the sural nerve, which was either intact or crushed 6-12 days before the experiment distal to the recording site. In all, 77 functionally identified afferent C-fibers (30 intact fibers, 47 injured fibers) and 34 functionally characterized A-fibers (11 intact fibers, 23 injured fibers) were tested for their responses to menthol applied to their receptive fields either in the skin (10 or 20%) or in the nerve (4 or 8 mM). Menthol activated all intact (n = 12) and 90% of injured (n = 20/22) type 1 cold-sensitive C-fibers; it activated no intact type 2 cold-sensitive C-fibers (n = 7) and 1/11 injured type 2 cold-sensitive C-fibers. Neither intact nor injured heat- and/or mechanosensitive cold-insensitive C-fibers (n = 25) and almost no A-fibers (n = 2/34) were activated by menthol. These results strongly argue that cutaneous type 1 cold-sensitive afferent fibers are nonnociceptive cold fibers that use the TRPM8 transduction channel.