Sensitization to Mechanical Stimulation by Inflammatory Mediators and by Mild Burn in Canine Visceral Nociceptors In Vitro

Abstract

Hyperalgesia to mechanical stimulation and heat is commonly observed in inflamed conditions. Although sensitization to heat is well documented and its mechanism has also been well studied, it remains unclear whether and how nociceptors are sensitized to mechanical stimulation. Therefore we conducted in vitro investigation of which inflammatory mediators (bradykinin, histamine, prostaglandin E2, and protons) sensitize nociceptors to suprathreshold mechanical stimulation and at what concentrations. In addition, we studied the effects of possible second messengers for these mediators downstream of the receptors and also the effects of mild burn. Single polymodal receptor activities were recorded in canine testis-spermatic nerve preparations excised from deeply anesthetized dogs. Mechanical stimulation was applied to the identified receptive field for 10 s with a servo-controlled mechanical stimulator. Bradykinin at 0.001 microM induced neither excitation nor facilitation of the mechanical response; however, it facilitated the mechanical response at 0.01 microM and higher, levels at which significant excitation was also induced by bradykinin alone. Histamine excited the nociceptor and sensitized it to mechanical stimulation at 10 microM and higher. PG E(2) also sensitized the mechanical response, but starting at 1 microM, without inducing excitation by itself. The effects of two possible intracellular messengers for these mediators were studied using forskolin (10 microM), which increases intracellular cAMP, and a protein-kinase-C-stimulating phorbol ester, phorbol 12,13-dibutyrate (0.1 microM). Both substances reversibly facilitated the mechanical response of testicular polymodal receptors. In contrast, low-pH solution (pH: 6.6-4.5) seldom induced excitation and failed to facilitate the mechanical response. After 55 degrees C, 30-s heat stimulation, testicular polymodal receptors were sensitized to mechanical stimulation. These results demonstrated that inflammatory mediators and burn sensitized nociceptor responses to mechanical stimulation and provide support for the idea that peripheral nociceptor sensitization is a mechanism involved in hyperalgesia to mechanical stimulation in inflamed tissues.

Sensitization and Activation of Intracranial Meningeal Nociceptors by Mast Cell Mediators

“…Such preferential activation is reminiscent of the effect of MC degranulation on C-unit meningeal nociceptors (Levy et al, 2007). We found that histamine also preferentially promotes mechanical sensitization of C-units, findings that are in agreement with its effect on testicular nociceptors (Koda and Mizumura, 2002). Our study further showed that both the activation and sensitization mediated by histamine are short-lived, suggesting that histamine alone may not be able to sustain the prolonged activation of meningeal nociceptors evoked by MCs degranulation.…”

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…However, in the same preparation, neither PGE 2 nor the "inflammatory soup" (composed of PGE 2 , bradykinin, histamine, and serotonin) caused a decrease in the mechanical von Frey threshold of the mechanosensitive C-fibers, and the responses to suprathreshold mechanical stimuli remained unaltered as well (403,639). In a study on polymodal nociceptors of the isolated dog testis, PGE 2 did not alter the von Frey threshold but increased the number of spike discharges evoked by mechanical stimulation and this effect was mimicked by forskolin (370). PGE 2 and/or PGI 2 caused a mechanical sensitization of articular afferents of the cat knee joint, rat ankle and knee joint (53, 54, 564,636,638).…”

Augmented Mechanical Response of Muscle Thin-Fiber Sensory Receptors Recorded from Rat Muscle–Nerve Preparations In Vitro After Eccentric Contraction

“…BK also lowered the mechanical threshold of muscle nociceptors in vivo (Mense and Meyer 1988) and sensitized visceral nociceptors to mechanical stimulus in vitro (Koda and Mizumura 2002). In addition, prostaglandin E2, histamine (Koda and Mizumura 2002), and ATP (Page et al 2000) are known to sensitize nociceptor responses to mechanical stimulus. All these substances also sensitize nociceptors to heat (Koda et al 1996;Kress and Guenther 1999;Mizumura et al 1993;Petho et al 2001;Yajima et al 2005), although the concentration needed to sensitize sensory receptors to mechanical stimulus is higher than that needed to sensitize them to heat (Koda et al 2002).…”

“…Treatment with low pH was found to cause a significant and lasting decrease of the mechanical thresholds in almost all C-fibers in rat skin-nerve preparations in vitro (Steen et al 1992). BK also lowered the mechanical threshold of muscle nociceptors in vivo (Mense and Meyer 1988) and sensitized visceral nociceptors to mechanical stimulus in vitro (Koda and Mizumura 2002). In addition, prostaglandin E2, histamine (Koda and Mizumura 2002), and ATP (Page et al 2000) are known to sensitize nociceptor responses to mechanical stimulus.…”

“…In addition, prostaglandin E2, histamine (Koda and Mizumura 2002), and ATP (Page et al 2000) are known to sensitize nociceptor responses to mechanical stimulus. All these substances also sensitize nociceptors to heat (Koda et al 1996;Kress and Guenther 1999;Mizumura et al 1993;Petho et al 2001;Yajima et al 2005), although the concentration needed to sensitize sensory receptors to mechanical stimulus is higher than that needed to sensitize them to heat (Koda et al 2002). This result might suggest that the above substances are unlikely to be responsible for the sensitization to mechanical stimulus in the ECC group because the heat sensitivities were not altered in the present experiment.…”