- Email: [email protected]
Color Plates
P
1cm
<40
40–80
80–120 120–160
>160
Plate 1. Blood flow images during stimulation of fine nerve filaments containing C-heat nociceptor axons in the pig. Upper field: filament contained three identified heat nociceptors – afferent receptive fields outlined in red and one polymodal nociceptor (P) receptive field outlined in green. Note that only the heat nociceptors gave vasodilator responses. Lower two fields: filaments with one heat nociceptor axon. Note the good relation between afferent receptive field and area of vasodilatation. Images have been scaled so that color levels represent fixed percentages above the average baseline level and have been oriented so that proximal is to the right and anterior at the top. Scans took 1–3 min. Stimulation was 1–2 Hz for the duration of the scans (from Ref. [16]). (See Figure 1 of Chapter 2, p. 41).
Sensory nerve ending PAR-2 Mast cell tryptase
PL / PKC
Bradykinin receptor
H1
Histamine
SP P TR
CB1
V1
SP Endocannabinoids
NK-1
R
?
Mast cell
TRPV1 Inflammatory soup
Plate 2. Hypothetical interaction of TRPV1-expressing sensory afferents with mast cells. During inflammation, numerous mediators are generated, including bradykinin, prostaglandin, and protons. This “inflammatory soup” can directly activate TRPV1 (e.g., low pH) or indirectly sensitize TRPV1 (e.g., bradykinin through its receptor, bradykinin R). Activation of TRPV1 in sensory afferents results in the release of neuropeptides, including substance P (SP). SP via NK1 can activate mast cells resulting in the release of mast cell tryptase – an activator of PAR2. Sensitization of TRPV1 via PAR2 and/or histamine receptor (H1) would complete a positive regulatory loop between mast cells and sensory afferents that drives neurogenic inflammation. Endocannabinoids, such as anandamide, may activate sensory neurons through direct interaction with TRPV1(+) or decrease sensory neuron activity via cannabinoid receptor, CB1( ). PL, phospholipase; PKC, protein kinase C. (See Figure 1 of Chapter 5, p. 108).
SENSORY AFFERENT
Mast cell degranulation
Vasodilatation Chemotaxis
AUTONOMIC EFFERENT
Plasma extravasation
Plate 3. The axon reflex as first proposed by Lewis. Stimulation of primary afferent terminals results in orthodromic action potentials conducted to the CNS. Invasion of primary afferent terminal branches by antidromic action potentials (arrows) results in the release of proinflammatory neuropeptides such as substance P and calcitonin gene-related peptide (CGRP). These act on arterioles to cause vasodilatation (CGRP), on capillaries and postcapillary venules to cause plasma extravasation, on mast cell resulting in degranulation, and attract leukocytes out of the bloodstream (chemotaxis). Autonomic fibers may also release neuropeptide Y and vasoactive intestinal polypeptide, which also cause vasodilatation. (See Figure 1 of Chapter 10, p. 212).
Hypothalamus Vagal afferents
Anterior pituitary
Celiac branch
Adrenal
Epinephrine
Synovium
Corticosterone
Visceral afferents
C-fiber
Somatic afferents
Mast cell Bradykinin Pro-inflammatory mediators (e.g. PGE2)
Sympathetic fibers
Norepinephrine and Neuropeptide Y
Extravasation
Substance P and CGRP Histamine/serotonin
Plate 4. Production of synovitis by bradykinin. Bradykinin acts on B2 or B1 bradykinin receptors on the sympathetic postganglionic neuron to release pro-inflammatory mediators. These inflammatory mediators (e.g., prostaglandin E2) are released independent of electrical activity of the sympathetic neuron, and act directly on the postcapillary venule and/or on other cell types associated with the sympathetic neuron. Bradykinin can also act directly on its receptors on C-fiber neurons to release proinflammatory mediators (e.g., substance P). Sympathetic C-fiber peptidergic coupling is bidirectional, with norepinephrine/neuropeptide Y acting on C-fibers and substance P/CGRP acting on sympathetic neuron terminals. Two neuroendocrine pathways, HPA and sympathoadrenal, that are activated by ongoing noxious input from inflammatory sites, mediate a negative feedback control of inflammation by releasing mediators (e.g., glucocorticoids and epinephrine); these circuits are tonically inhibited by activity in duodenal vagal afferents, exerted at the level of the spinal cord [144]. Immune cells, which play an essential role in the inflammatory response, are attracted to the synovium and activated by mediators released from sympathetic and C-fiber afferent neurons as well as by bradykinin and other tissue-generated inflammatory mediators. Other mechanisms, including the proinflammatory and anti-inflammatory cytokine network, sympathetic innervation of lymphoid organs [214], and the anti-inflammatory cholinergic efferent vagal pathway [215], contribute to the pathophysiology of synovial inflammation, but for the sake of clarity are not included in this schematic figure. (See Figure 4 of Chapter 11, p. 253).
1cm
<40
40–80
80–120 120–160
>160
Plate 1. Blood flow images during stimulation of fine nerve filaments containing C-heat nociceptor axons in the pig. Upper field: filament contained three identified heat nociceptors – afferent receptive fields outlined in red and one polymodal nociceptor (P) receptive field outlined in green. Note that only the heat nociceptors gave vasodilator responses. Lower two fields: filaments with one heat nociceptor axon. Note the good relation between afferent receptive field and area of vasodilatation. Images have been scaled so that color levels represent fixed percentages above the average baseline level and have been oriented so that proximal is to the right and anterior at the top. Scans took 1–3 min. Stimulation was 1–2 Hz for the duration of the scans (from Ref. [16]). (See Figure 1 of Chapter 2, p. 41).
Sensory nerve ending PAR-2 Mast cell tryptase
PL / PKC
Bradykinin receptor
H1
Histamine
SP P TR
CB1
V1
SP Endocannabinoids
NK-1
R
?
Mast cell
TRPV1 Inflammatory soup
Plate 2. Hypothetical interaction of TRPV1-expressing sensory afferents with mast cells. During inflammation, numerous mediators are generated, including bradykinin, prostaglandin, and protons. This “inflammatory soup” can directly activate TRPV1 (e.g., low pH) or indirectly sensitize TRPV1 (e.g., bradykinin through its receptor, bradykinin R). Activation of TRPV1 in sensory afferents results in the release of neuropeptides, including substance P (SP). SP via NK1 can activate mast cells resulting in the release of mast cell tryptase – an activator of PAR2. Sensitization of TRPV1 via PAR2 and/or histamine receptor (H1) would complete a positive regulatory loop between mast cells and sensory afferents that drives neurogenic inflammation. Endocannabinoids, such as anandamide, may activate sensory neurons through direct interaction with TRPV1(+) or decrease sensory neuron activity via cannabinoid receptor, CB1( ). PL, phospholipase; PKC, protein kinase C. (See Figure 1 of Chapter 5, p. 108).
SENSORY AFFERENT
Mast cell degranulation
Vasodilatation Chemotaxis
AUTONOMIC EFFERENT
Plasma extravasation
Plate 3. The axon reflex as first proposed by Lewis. Stimulation of primary afferent terminals results in orthodromic action potentials conducted to the CNS. Invasion of primary afferent terminal branches by antidromic action potentials (arrows) results in the release of proinflammatory neuropeptides such as substance P and calcitonin gene-related peptide (CGRP). These act on arterioles to cause vasodilatation (CGRP), on capillaries and postcapillary venules to cause plasma extravasation, on mast cell resulting in degranulation, and attract leukocytes out of the bloodstream (chemotaxis). Autonomic fibers may also release neuropeptide Y and vasoactive intestinal polypeptide, which also cause vasodilatation. (See Figure 1 of Chapter 10, p. 212).
Hypothalamus Vagal afferents
Anterior pituitary
Celiac branch
Adrenal
Epinephrine
Synovium
Corticosterone
Visceral afferents
C-fiber
Somatic afferents
Mast cell Bradykinin Pro-inflammatory mediators (e.g. PGE2)
Sympathetic fibers
Norepinephrine and Neuropeptide Y
Extravasation
Substance P and CGRP Histamine/serotonin
Plate 4. Production of synovitis by bradykinin. Bradykinin acts on B2 or B1 bradykinin receptors on the sympathetic postganglionic neuron to release pro-inflammatory mediators. These inflammatory mediators (e.g., prostaglandin E2) are released independent of electrical activity of the sympathetic neuron, and act directly on the postcapillary venule and/or on other cell types associated with the sympathetic neuron. Bradykinin can also act directly on its receptors on C-fiber neurons to release proinflammatory mediators (e.g., substance P). Sympathetic C-fiber peptidergic coupling is bidirectional, with norepinephrine/neuropeptide Y acting on C-fibers and substance P/CGRP acting on sympathetic neuron terminals. Two neuroendocrine pathways, HPA and sympathoadrenal, that are activated by ongoing noxious input from inflammatory sites, mediate a negative feedback control of inflammation by releasing mediators (e.g., glucocorticoids and epinephrine); these circuits are tonically inhibited by activity in duodenal vagal afferents, exerted at the level of the spinal cord [144]. Immune cells, which play an essential role in the inflammatory response, are attracted to the synovium and activated by mediators released from sympathetic and C-fiber afferent neurons as well as by bradykinin and other tissue-generated inflammatory mediators. Other mechanisms, including the proinflammatory and anti-inflammatory cytokine network, sympathetic innervation of lymphoid organs [214], and the anti-inflammatory cholinergic efferent vagal pathway [215], contribute to the pathophysiology of synovial inflammation, but for the sake of clarity are not included in this schematic figure. (See Figure 4 of Chapter 11, p. 253).