Research reportResponses of primary afferents and spinal dorsal horn neurons to thermal and mechanical stimuli before and during zymosan-induced inflammation of the rat hindpaw
Introduction
Inflammation is most often associated with either tissue damage or nerve injury. Common signs of inflammation include redness, swelling, and primary hyperalgesia. Primary hyperalgesia is characterized by a lowering of response threshold and/or an increased response to supra-threshold stimuli at the site of injury. This is typically manifested to both mechanical and thermal stimuli, and it is generally held that alterations in both peripheral and central nervous system processes are critical for the production of primary hyperalgesia (cf., 6, 8, 30).
Primary hyperalgesia can result from sensitization of primary nociceptors, or an increase in the excitability of peripheral nociceptors to mechanical and thermal stimuli at the inflammatory site. Sensitization often depends on the release, synthesis, or attraction of inflammatory mediators to the site of injury 7, 20, 22, 28. However, the precise mechanisms by which peripheral nociceptors are sensitized, the specific types of peripheral nociceptors that are affected, and the relationship of these peripheral changes to events occurring in the central nervous system during inflammation are not well characterized.
It also has been suggested that either the initial discharge or sensitization of primary nociceptors can lead to some form of central plasticity of spinal dorsal horn neurons. This may either augment or unmask input from primary afferents/nociceptors. This view is applied most often to secondary hyperalgesia, which typically affects the response of uninjured tissue surrounding the site of injury, and primarily is manifested to mechanical stimuli 12, 22, 27, 29. However, this hypothesis applies equally well to issues of primary hyperalgesia. Recent data suggests that central plasticity may depend on the release of excitatory amino acids (EAA) and/or tachykinins, but there remains considerable controversy about the receptor subtypes and intracellular cascades which are involved in this central plasticity 6, 14.
A variety of animal models have been developed to study hyperalgesia resulting from inflammation. The present study examined one model which involves intraplantar injection of zymosan into the rat hindpaw. Behavioral studies have shown that zymosan administration produces a time- and dose-dependent cutaneous hyperalgesia to both mechanical and thermal stimuli 15, 16, 17, 18. This model has many desirable features for performing electrophysiological analyses of neuronal changes occurring during hyperalgesia resulting from inflammation. First, the hyperalgesia develops rapidly and enables analyses of activity changes within a neuron over time rather than relying on less-desirable population studies. Second, it is stable over relatively long periods of time, thereby enabling the necessary time frames in which to perform important, stimulus-response function (SRF) analyses. Third, pharmacological data obtained in behavioral studies suggest that different mechanisms may mediate the development of hyperalgesia to either mechanical or thermal stimuli 14, 16, 17. An understanding of these differences may provide unique insights into the mechanisms responsible for inflammation-induced changes in pain sensitivity.
Since zymosan-induced inflammation is being examined in behavioral studies of both cutaneous hyperalgesia and, more recently, visceral primary hyperalgesia 3, 4, 5, the goal of the present studies was to determine how primary afferents and spinal dorsal horn neurons were affected by intraplantar administration of zymosan in the rat. These single unit, time-course studies determined response thresholds to mechanical and thermal stimuli, total discharges during sustained mechanical and thermal stimuli, and changes in background activity before and during zymosan-induced inflammation. Preliminary reports of these data have been previously published as abstracts 23, 24.
Section snippets
Subjects
Male Sprague-Dawley rats were obtained from Harlan in Pratville, AL. Rats were housed in plastic cages under a 12 : 12 h light-dark cycle. Food and water were available on an ad libitum basis. All rats weighed between 350–450 g at the time of testing. All studies were approved by the Animal Care and Use Committees at the University of Iowa and the University of Alabama at Birmingham.
Apparatus
Primary afferents were recorded monopolarly by placing a fine filament of a nerve bundle over one pole of bipolar
Primary afferents
LTM<1.0 g (n=6), LTM>1.0 g (n=8), HTM (n=17), AMH (n=8), CMH (n=9), and CMN (n=7) units were studied in experiments with mechanical stimuli. Zymosan administration differentially affected the response thresholds and total discharges of these units and are analyzed separately below. Fig. 1 shows the analysis of group mean mechanical response thresholds and Fig. 2 shows the analyses of group mean total discharges during 10 s of mechanical stimulation for each class of unit.
The group mean response
Discussion
Zymosan is a carbohydrate-rich cell wall preparation obtained from Saccharomyces cerevisiae. Zymosan administration induces a wide-variety of inflammatory and immune responses depending on the route of administration. It has been used extensively to model many disease processes ranging from rheumatoid arthritis to multiple organ system dysfunction. More recently, zymosan has been used in the area of pain research in behavioral studies of hyperalgesia involving either cutaneous or visceral
Acknowledgements
This research was supported by NIH award DA 02879 to G.F. Gebhart and an award from the Procter and Gamble Company to A. Randich. We also thank Dr J. Cox for use of his computer programs for data analysis.
References (30)
- et al.
Intracolonic zymosan produces visceral hyperalgesia in the rat that is mediated by spinal NMDA and non-NMDA receptors
Brain Res.
(1996) - et al.
Expansion of receptive fields of spinal lamina I projection neurons in rats with unilateral adjuvant-induced inflammation: the contribution of dorsal horn neurons
Pain
(1989) - et al.
The effect of carrageenan-induced inflammation on the sensitivity of unmyelinated skin nociceptors in the rat
Pain
(1987) Thermal and mechanical hyperalgesia. A distinct role for different excitatory amino acid receptors and signal transduction pathways
APS Journal
(1994)- et al.
The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat
Neuropharmacology
(1994) - et al.
Acute thermal hyperalgesia is produced by activation of NMDA receptors, production of nitric oxide and CGMP and activation of protein kinase C
Neuroscience
(1996) - et al.
Electrophysiological characteristics of dorsal horn cells in rats with cutaneous inflammation resulting from chronic arthritis
Pain
(1982) - et al.
Does neurogenic inflammation alter the sensitivity of unmyelinated nociceptors in the rat
Brain Res.
(1986) - et al.
Peripheral and central mechanisms of cutaneous hyperalgesia
Prog. Neurobiol.
(1992) - et al.
Neurogenic hyperalgesia: The search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia
J. Neurophysiol.
(1991)
Intracolonic zymosan produces inflammation and visceral hyperalgesia in the rat
Soc. Neurosci. Abstr.
Involvement of nitric oxide in zymosan-produced visceral hyperalgesia in the rat
Soc. Neurosci. Abstr.
Cited by (30)
Percutaneous electrical nerve field stimulation modulates central pain pathways and attenuates post-inflammatory visceral and somatic hyperalgesia in rats
2017, NeuroscienceCitation Excerpt :A total of six neurons that responded to somatic stimulation (compression of the hind paw) were recorded before and after stimulation with the BRIDGE. All neurons recorded from CeA were nociceptive-specific, since they exhibited responses only to noxious pinch (Randich et al., 1997). Fig. 5A, B shows examples of one CeA neuron before and after PENFS.
The prickly, stressful business of burn pain
2014, Experimental NeurologySeparate groups of dorsal horn neurons transmit spontaneous activity and mechanosensitivity one day after plantar incision
2009, European Journal of PainCitation Excerpt :A variety of forms of central sensitization can be induced by peripheral nociceptor activation (Woolf and Salter, 2000; Ji et al., 2003). In persistent pain states, sensitization of dorsal horn neurons (DHNs) has been reported in several models such as hind paw inflammation (Ren et al., 1992; Randich et al., 1997), arthritis pain (Schaible et al., 1991; Sharif Naeini et al., 2005), cancer pain (Urch et al., 2003; Khasabov et al., 2007), and neuropathic pain model (Pertovaara et al., 1997; Chapman et al., 1998). Perhaps the most powerful form of dorsal horn neuron sensitization is increased ongoing activity or spontaneous activity.
Tumor-evoked hyperalgesia and sensitization of nociceptive dorsal horn neurons in a murine model of cancer pain
2007, Brain ResearchCitation Excerpt :Pentobarbital may affect the electrophysiological properties of nociceptive dorsal horn neurons differently than halothane (Hori et al., 1984). Differential sensitization of WDR but not HT neurons observed in our study and by Dickenson and colleagues (Urch et al., 2003) may be unique to cancer pain in that both WDR and HT neurons exhibit increased levels of ongoing activity in models of incisional pain (Vandermeulen and Brennan, 2000), arthritis (Grubb et al., 1993; Neugebauer and Schaible, 1990), paw inflammation (Randich et al., 1997), skin freeze injury (Khasabov et al., 2001), activation of C nociceptors by mustard oil (Woolf et al., 1994), capsaicin-evoked pain (Johanek and Simone, 2005; Simone et al., 1989), and neuropathic pain (Sotgiu et al., 1994). Furthermore, recent studies have demonstrated that neurochemical changes in the spinal cord of mice with tumor-evoked hyperalgesia differ from those in mice with hyperalgesia produced by inflammation or nerve injury (Honore et al., 2000).
Dorsal horn neuron response patterns to graded heat stimuli in the rat
2005, Brain Research