Carrageenan inflammation increases bradykinin sensitivity of rat cutaneous nociceptors

doi:10.1016/0304-3940(90)90369-K

Neuroscience Letters

Volume 111, Issues 1–2, 26 March 1990, Pages 206-210

https://doi.org/10.1016/0304-3940(90)90369-K Get rights and content

Abstract

The present study examined the hypothesis that the sensitivity of polymodal nociceptors to bradykinin (BK) might be increased in inflamed tissue. Inflammation was induced in the rat dorsal hindpaw skin by subcutaneous injection of blue stained carrageenan. Three hours later skin and saphenous nerve were excised and the chemical sensitivity of mechano-heat-sensitive C- and Aδ fibres was examined in vitro using repeated superfusion of the receptive fields with 10⁻⁵ M BK. Only units within and at the border of the inflamed area showed signs of sensitization, in the form of ongoing activity and lower thresholds to heat stimuli. No sensitization to mechanical (von Frey) stimulation occurred. The incidence of BK responsiveness was significantly higher and the tachyphylaxis to repeated BK application was smaller inside the inflamed skin than outside or in unconditioned skin. Thus, more nociceptive afferents would be driven more effectively than in normal skin, supporting the particular role of BK in inflammatory pain.

References (19)

H.A. Al-Haboubi et al.
Re-appraisal of the role of histamines in carrageenan-induced paw oedema
Eur. J. Pharmacol.
(1983)
W.C. Chang et al.
Differences in the mode of exudative reaction between early phase and late phase of carrageenan-induced inflammation in rats
Eur. J. Pharmacol.
(1976)
L. Kocher et al.
The effect of carrageenan-induced inflammation on the sensitivity of unmyelinated skin nociceptors in the rat
Pain
(1987)
P.W. Reeh
Sensory receptors in mammalian skin in an in vitro preparation
Neurosci. Lett.
(1986)
R.E. Beitel et al.
Sensitization and depression of C- polymodal nociceptors by noxious heat applied to the monkey's face
P. Bessou et al.
Response of cutaneous sensory units with unmyelinated fibres to noxious stimuli
J. Neurophysiol.
(1969)
F. Capasso et al.
Further studies on carrageenan-induced pleurisy in rats
J. Pathol.
(1975)
S. Croze et al.
The thermal sensitivity of the polymodal nociceptors in the monkey
J. Physiol. (Lond.)
(1976)
M. Fitzgerald et al.
The sensitization of high-threshold mechano-receptor with myelinated axons by repeated heating
J. Physiol. (Lond.)
(1977)

There are more references available in the full text version of this article.

Cited by (44)

Sensitization of primary afferents to mechanical and heat stimuli after incision in a novel in vitro mouse glabrous skin-nerve preparation
2008, Pain
Citation Excerpt :
This is a topic we have not addressed. Many previous studies failed to identify mechanical sensitization after experimental pathological conditions [3,15,22,28,30]. This led to the hypothesis that sensitization to mechanical stimuli is purely a central phenomenon or sensitization occurring due to recruitment of mechano-insensitive units, which develop novel mechanosensitivity after injury [30].
In this study, we recorded activity from afferent fibers innervating the mouse plantar skin, the same region evaluated in pain behavior experiments. We compared responses of afferents from incised and unincised hind paw skin. The plantar skin together with attached medial and lateral plantar nerves was dissected until they could be completely removed intact and placed in an organ bath chamber continuously perfused with oxygenated Kreb’s solution with the temperature maintained at 32 °C. Afferent nerve activities to feedback-controlled mechanical and heat stimuli and cooling were recorded. Eighty-five single Aδ- and C-fiber afferents were recorded, 42 from control and the remainder from incised animals. A greater proportion of C-fibers (11/34) from incised skin had spontaneous activity than in the unincised preparation (2/32). The mechanical thresholds of both Aδ- and C-fiber units were not different between control and incised groups but the responses to suprathreshold mechanical stimulation were increased in low threshold Aδ- and C-fibers. The greatest change in heat sensitivity was apparent when multi-fiber total activity was measured; threshold was reduced, total spikes were greater and the peak discharge frequency was increased. In summary, feedback-controlled stimulation identified mechanical sensitization after incision in an in vitro preparation. Few fibers were excited by cooling. Heat sensitization of primary afferents was more prominent when activities of unclassified afferents are included. The preparation allows us to study afferent function of the same tissue that is examined for in vivo pain behavior assays in mice.
Chapter 3 The Nociceptive Membrane: Historical Overview
2006, Current Topics in Membranes
Citation Excerpt :
Presumably, itch transduction depends on the activation of histamine receptors on this specific group of sensory neurons. Nociceptors can be sensitized following strong noxious stimuli or by exposure to inflammatory mediators or low pH (Bessou and Perl, 1969; Fitzgerald and Lynn, 1977; Meyer and Campbell, 1981; LaMotte et al., 1982, 1983; Kocher et al., 1987; Reeh et al., 1987; Häbler et al., 1990; Kirchhoff et al., 1990; Handwerker et al., 1991; Schmelz et al., 1996; Willis and Coggeshall, 2004). The following substances can induce sensitization of nociceptors by interactions with surface membrane receptors: bradykinin (Rueff and Dray, 1993a; Schuligoi et al., 1994; Liang et al., 2001; Shin et al., 2002); catecholamines (Gold et al., 1994; Khasar et al., 1999); cytokines (Sorkin et al., 1997); excitatory amino acids (Ferreira and Lorenzetti, 1994; Du et al., 2001); inflammatory soup (a mixture of bradykinin, histamine, serotonin, and prostaglandin E1) (Kessler et al., 1992; Davis, et al., 1993; Kress et al., 1997); neurokinins and other peptides (Nakamura‐Craig and Gill, 1991; Kessler et al., 1992); prostaglandins and other arachidonic acid products (Martin et al., 1987; Cohen and Perl, 1990; Martin, 1990; White et al., 1990; Schepelmann et al., 1992; Rueff and Dray, 1993a,b; Chen et al., 1999); protons (Steen et al., 1992, 1996); and serotonin (Rueff and Dray, 1993b).
This chapter provides an overview of the nociceptive membrane. Nociceptors are primary afferent neurons that signal tissue damage or the threat of tissue damage. Nociceptors are found in the skin and subcutaneous tissue, muscle, joints, and viscera. They also supply the meninges, although they do not intrude into the central nervous system (CNS). Nociceptors have unencapsulated terminals in the tissue that they innervate. The axons of cutaneous nociceptive afferents are either ﬁnely myelinated (Aδ) or unmyelinated (C) ﬁbers. Nociceptors that supply muscle or joints are also finely myelinated and unmyelinated afferents, but a different nomenclature is used; these are referred to as group III and group IV fibers. Although the terminals of nociceptors are often described as “free nerve endings,” much of the terminal membrane of nociceptors is covered by Schwann cells. However, there are membrane areas that are exposed to the extracellular space. The ability of an individual nociceptor to respond to different types of noxious stimuli would depend on the presence or absence of particular transduction molecules in its surface membrane.
Kainate-induced excitation and sensitization of nociceptors in normal and inflamed rat glabrous skin
2006, Neuroscience
This study investigates contributions of peripheral kainate receptors to acute nociception and persistent inflammatory pain in rat. Immunohistochemical analysis of kainate receptor expression using antibodies recognizing glutamate receptor subunits 5, 6, and 7 demonstrates that 28% of unmyelinated axons in normal digital nerve are positively labeled. Following intraplantar injection of complete Freund’s adjuvant, a significant increase in glutamate receptor subunits 5, 6, and 7-labeled axons occurs at 2 days (40%), but not 7 (31%) or 14 days (28%) post-complete Freund’s adjuvant. In behavioral studies, we confirm an increased mechanical sensitivity in complete Freund’s adjuvant-injected hind paws. Furthermore, activation of kainate receptors following intraplantar injection of 1.0mM kainate in normal animals results in a mechanical sensitivity similar to that observed in inflamed animals. A 1.0mM kainate injection into inflamed hind paws further enhances the mechanical sensitivity. Injection of the non–N-methyl-d-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (0.1mM) reverses complete Freund’s adjuvant-induced mechanical sensitivity through a local effect. In single unit recordings from nociceptors in a glabrous skin-nerve preparation, mechanical sensitization is present in inflamed skin evidenced by a decrease in mechanical threshold and an increase in discharge rate during a suprathreshold, constant force stimulus. Thermal sensitization is also present evidenced by a decrease in heat threshold. There is a dose-dependent increase in kainate-induced nociceptor activity in both normal and inflamed skin but the kainate required to induce activation is reduced in inflamed skin. Although proportions of kainate-activated nociceptors are the same in normal and inflamed skin, the kainate-induced mean discharge rate is significantly enhanced in inflamed skin. Exposure of normal and inflamed nociceptors to 0.3mM kainate sensitizes fibers to re-application of kainate and heat. This sensitization is blocked in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione or the glutamate receptor subunit 5 selective antagonist 3S,4aR,6S,8aR-6-[4-carboxy-phenyl] methyl-1,2,3,4,4a,5,6,7,8,8a-deca-hydroisoquinoline-3-carboxylic acid. The data indicate that peripheral kainate receptors not only play an important role in normal nociception but also contribute to mechanical sensitivity and heat sensitization accompanying inflammatory pain.
Spontaneous discharge and increased heat sensitivity of rat C-fiber nociceptors are present in vitro after plantar incision
2004, Pain
Postoperative pain is characterized by spontaneous pain at the surgical site and increased pain due to movements. To study postoperative pain mechanisms, we investigated discharge properties of mechano-heat sensitive C-fiber afferents innervating the rat glabrous hindpaw skin 1 day after plantar incision. Behaviors indicating spontaneous pain, heat and mechanical hyperalgesia were present 1 day after incision. Recording of afferents using in vitro glabrous skin-nerve preparation showed that more C-fibers from the incision had spontaneous discharge than control rats. The spontaneously discharging fibers from incised rats had lower heat response threshold compared with fibers without spontaneous activity. In all fibers less than 2 mm from the incision, an increased percentage responded to lower temperatures (35–41 °C), the mean heat response threshold was 3.1 °C less, the stimulus–response function for heat evoked response was shifted to the left and the total number of impulses in response to a 33–48 °C heat stimulus was increased. Heat responses of C-fibers more than 2 mm from the incision, however, were not different from control. The mean mechanical response thresholds, measured by a servo force-controlled stimulator, were not different between groups. The total spikes evoked at supra-threshold mechanical stimulation were not increased in afferents from the incision. In conclusion, 1 day after incision, when behaviors indicating spontaneous pain, heat and mechanical hyperalgesia are present, C-fibers close to incision showed spontaneous discharge and sensitization to heat but not to mechanical stimuli, in vitro.
Subtypes of nociceptive units in the rat temporomandibular joint
2003, Brain Research Bulletin
Response properties of nociceptors in the rat’s temporomandibular joint (TMJ) were investigated using an in vitro TMJ-nerve preparation. Recordings were obtained from 33 nociceptive units that responded to mechanical, chemical, and/or thermal stimuli. According to both characteristics of nociceptors and afferent fibers, nociceptive units in the TMJ area were classified into the following four subtypes: Aδ-high-threshold mechanonociceptor (HTM) (12.1%), Aδ-polymodal nociceptor (POLY) (36.4%), C-HTM (12.1%), and C-POLY (39.4%). The mean mechanical threshold of the Aδ units was significantly lower than that of the C units. Bradykinin increased the discharge of Aδ- and C-POLY units. No significant differences of thermal thresholds between Aδ and C units were found. The percentage of Aδ units was 47.2% and of C units was 52.8%, respectively. In the TMJ area, POLY units were predominant (75.8%), suggesting that inflammatory reactions can easily evoke pain sensation.
N-methyl-D-aspartate-induced excitation and sensitization of normal and inflamed nociceptors
2003, Neuroscience
The present study investigates the contribution of peripheral N-methyl-d-aspartate (NMDA) receptors to acute nociception and persistent inflammatory pain in the rat. Immunohistochemical localization of the NMDA receptor one (NMDAR1) subunit demonstrates that 47% of unmyelinated axons in the normal digital nerve are positively labeled. In concert with the overall progression of inflammation following injection of complete Freund’s adjuvant (CFA) in the hind paw, a significant increase in the proportion of NMDAR1-labeled unmyelinated digital axons occurs at 2 and 7, but not 14 days following hind-paw inflammation. In behavioral studies, we confirm an increased mechanical sensitivity in CFA-injected hind paws. Furthermore, activation of NMDA receptors following intraplantar NMDA (1.0 mM) in normal animals results in a mechanical sensitivity similar to that observed in inflamed animals. Conversely, a low concentration of NMDA (0.5 mM) that has little affect on mechanical thresholds in normal animals produces a significant increase in mechanical sensitivity in the inflamed state. CFA-induced mechanical sensitivity involves NMDA-receptor activation demonstrated by the observation that injection of MK-801 alone into the inflamed hind paw returns mechanical sensitivity to normal (pre-inflammation) levels. In single-unit studies, there is a dose-dependent increase in NMDA-induced nociceptor activity in both normal and inflamed skin, but the amount of NMDA required to induce activation is reduced in inflamed skin. In addition, NMDA-induced discharge rates and percentage of NMDA-activated nociceptors are significantly increased in inflamed compared with normal skin, and this activation can be blocked by co-administration of MK-801. Exposure of nociceptors in normal skin to 1 mM NMDA sensitizes the units to reapplication of NMDA and to heat. Nociceptors that demonstrate sensitization to heat in persistent inflammation show an enhanced sensitization when exposed to exogenous NMDA. Thus, peripheral NMDA receptors not only play an important role in modulating the responses of nociceptors in normal skin, but their upregulation and activation on peripheral nociceptors contributes significantly to the mechanical sensitivity and heat sensitization that accompanies persistent inflammation.

View all citing articles on Scopus

View full text

Carrageenan inflammation increases bradykinin sensitivity of rat cutaneous nociceptors

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pain

Neurosci. Lett.

Sensitization and depression of C- polymodal nociceptors by noxious heat applied to the monkey's face

Response of cutaneous sensory units with unmyelinated fibres to noxious stimuli

J. Neurophysiol.

Further studies on carrageenan-induced pleurisy in rats

J. Pathol.

The thermal sensitivity of the polymodal nociceptors in the monkey

J. Physiol. (Lond.)

The sensitization of high-threshold mechano-receptor with myelinated axons by repeated heating

J. Physiol. (Lond.)