Vagotomy-Induced Enhancement of Mechanical Hyperalgesia in the Rat Is Sympathoadrenal-Mediated

Abstract

We have recently shown that subdiaphragmatic vagotomy enhances bradykinin-induced hyperalgesic behavior and decreases baseline paw withdrawal threshold to mechanical stimulation of the hindpaw skin in rats by a peripheral mechanism. To elucidate the underlying mechanism, we studied whether lesions of efferent neuroendocrine pathways could prevent or reverse the potentiating effect of vagotomy. In groups of shamvagotomized or vagotomized rats, we surgically removed or denervated the adrenal medulla. Bradykinin was injected intradermally into the skin of the dorsal surface of the rat hindpaw. Threshold of paw withdrawal to mechanical stimulation of the skin was measured.Vagotomy induced a decrease in mechanical baseline paw withdrawal threshold and enhancement of bradykinin-induced mechanical hyperalgesic behavior, both of which were maintained over the 5 week testing period. Adrenal enucleation or denervation of the adrenal gland by suprarenal ganglionectomy prevented vagotomy-induced decrease in baseline paw withdrawal threshold and enhancement of bradykinin-induced hyperalgesia. In animals that had a demonstrated decrease in baseline paw withdrawal threshold and enhancement of bradykinin-induced hyperalgesia 2 weeks after vagotomy, additional denervation of the adrenal medulla significantly reversed these effects over a 3 week period.These results imply that both the decrease in baseline paw withdrawal threshold and enhancement of bradykinin-induced hyperalgesic behavior after vagotomy are dependent on a hormonal signal released from the adrenal medulla and suggest a novel mechanism of sensitization of cutaneous nociceptors. Key words: bradykinin; hyperalgesia; nociception; pain; sympathoadrenal system; vagusIn the rat, activity in vagal afferents from abdominal organs modulates transmission of nociceptive impulses in the spinal cord and probably elsewhere in the C NS and also affects experimental pain behavior Randich and Gebhart, 1992; Watkins and Maier, 1995a,b). Recently, we have shown that bradykinin (BK)-induced mechanical cutaneous hyperalgesia is significantly enhanced after subdiaphragmatic vagotomy. A similar effect was seen after cutting the celiac branches of the abdominal vagus nerve but not after cutting only its gastric and hepatic branches. Furthermore, baseline mechanical paw withdrawal threshold decreased after vagotomy. The enhanced mechanical hyperalgesia produced by subdiaphragmatic vagotomy was specific for hyperalgesia induced by BK . Hyperalgesia induced by the direct-acting hyperalgesic agent prostaglandin E 2 (PGE 2 ) was not affected by vagotomy (K hasar et al., 1997). These findings argue that enhancement of BK-induced mechanical hyperalgesia and decrease in baseline mechanical paw withdrawal threshold after abdominal vagotomy are produced by a peripheral mechanism. However, as the experimental results reported in this manuscript show, we do not exclude a central component in enhancement of BK-induced hyperalgesia after vagotomy, as predicted by the work of Gebhart and Randich (1992)...

Stress Induces a Switch of Intracellular Signaling in Sensory Neurons in a Model of Generalized Pain

“…The present results do not implicate a mechanism for the delay, but it may be instructive to note that a similar delay in enhancement of hyperalgesia occurs in rats after subdiaphragmatic vagotomy (Khasar et al, 1998a), an effect also dependent on neuroendocrine stress axes (Khasar et al, 1998b(Khasar et al, , 2003b. Furthermore, whereas hyperalgesia is a component of inflammation, in our previous studies on the effect of nonhabituating sound stress in a model of inflammation, bradykinin-induced plasma extravasation from the knee joint, we found no evidence of the involvement of the HPA axis in sound-stress-induced suppression of plasma extravasation (Strausbaugh et al, 2003).…”

Animal Models of Fibromyalgia

“…Because unpredictable sound stress affects both axes and causes a prolonged elevation of plasma adrenaline levels, the stress-induced release of adrenaline (the product of neuroendocrine system activation) likely plays an important role in developing mechanical hyperalgesia in the unpredictable sound stress model. This working hypothesis is consistent with evidence of elevated plasma adrenaline levels and enhanced bradykinin-induced mechanical hyperalgesia in vagotomized rats (Khasar et al, 1998;Khasar et al, 2003;Levine and Reichling, 2005). Hypersensitivity in the presence of pronociceptive substances is commonly observed in fibromyalgia patients , and the requirement of pronociceptive substances for sound-stressed animals to exhibit enhanced somatosensory function may reflect a similar feature.…”

“…These models also reveal no apparent organic disorders that can explain the source of chronic pain symptoms, unlike neuropathic and inflammatory pain animal models. Biochemical and pharmacological studies have found that vagotomy in the stomach (subdiaphragmatic vagotomy) induces cutaneous (Khasar et al, 1998), visceral (Gschossmann et al, 2002) and muscle (Furuta et al, 2009) hyperalgesia in rats in a manner that resembles hyperalgesia in fibromyalgia patients. Chronic exposure to stressors other than those described above also produces enhanced nociception in animals.…”

Causalgia and reflex sympathetic dystrophy: Does the sympathetic nervous system contribute to the generation of pain?

“…Sensitization of nociceptive primary afferents by such proinflammatory mediators as bradykinin and nerve growth factor also depends on an intact sympathetic nervous system. 2,85,177 Levine and colleagues 84 have proposed that bradykinin, like norepinephrine, acts indirectly on nociceptor terminals by inducing the release of prostaglandins from sympathetic fibers (Fig. 4C).…”