Frederick Jia-Pei Miao

Vagal modulation of nociception is mediated by adrenomedullary epinephrine in the rat.

Vagal afferent activity modulates mechanical nociceptive threshold and inflammatory mediator‐induced hyperalgesia, effects that are mediated by the adrenal medulla. To evaluate the role of epinephrine, the major hormone released from the adrenal medulla, the β2‐adrenergic receptor antagonist ICI 118,551 was chronically administered to vagotomized rats and epinephrine to normal rats. In vagotomized rats, chronic administration of ICI 118,551 markedly attenuated vagotomy‐induced enhancement of bradykinin hyperalgesia but had no effect on nociceptive threshold. In normal rats, chronic epinephrine had the opposite effect, enhancing bradykinin hyperalgesia. Like vagotomy‐, epinephrine‐induced enhancement of hyperalgesia developed slowly, taking 14 days to reach its peak. Vagotomy induced a chronic elevation in plasma concentrations of epinephrine. We suggest that ongoing activity in vagal afferents inhibits the release of epinephrine from the adrenal medulla. Chronically elevated levels of epinephrine, occurring after vagotomy, desensitize peripheral β2‐adrenergic receptors and lead to enhancement of bradykinin hyperalgesia. The ability of prolonged elevated plasma levels of epinephrine to sensitize bradykinin receptors could contribute to chronic generalized pain syndromes.

Modulation of bradykinin-induced mechanical hyperalgesia in the rat by activity in abdominal vagal afferents

Bradykinin‐induced plasma extravasation and mechanical hyperalgesia are sympathetic‐dependent components of inflammation. Noxious stimulation has been found to inhibit bradykinin‐induced plasma extravasation by activating the hypothalamo‐pituitary‐adrenal axis. The sensitivity of this nociceptive‐neuroendocrine feedback control of inflammation is modulated by activity in subdiaphragmatic vagal afferents. In the present study, we tested the hypothesis that activity in the subdiaphragmatic vagus also modifies bradykinin‐induced mechanical hyperalgesia in the rat, using the Randall–Selitto method.

Chapter 20 - The role of vagal visceral afferents in the control of nociception

We have shown that activity in subdiaphragmatic vagal afferents modulates mechanical hyperalgesic behavior in the rat. Subdiaphragmatic vagotomy decreases paw-withdrawal threshold to mechanical stimulation (baseline and after intradermal injection of bradykinin), thus enhancing mechanical hyperalgesic behavior. Most of this decrease is generated by an endocrine signal released by the adrenal medullae because denervation or removal of the adrenal medullae prevents or reverses these changes. This novel mechanism may imply that: (a) the brain is able to regulate sensitivity of nociceptors all over the body by a neuroendocrine mechanisms, (b) sensitivity of nociceptors can be influenced by changes in parts of the body which are remote from the location of the sensitized nociceptors and (c) circulating catecholamines can influence nociceptors in a way which is different from those reported so far (see Jänig and McLachlan, 1994; Jänig, 1996a; Jänig et al., 1996).

Inflammation modulates the contribution of receptor-subtypes to bradykinin-induced hyperalgesia in the rat

While B2 receptors mediate pain and hyperalgesia induced by bradykinin, in normal rats, recent reports indicate that, in the setting of inflammation, B1 receptors also mediate pain and hyperalgesia. Since bradykinin-induced hyperalgesia in normal rats is mediated by prostaglandins released from the postganglionic sympathetic neurons, we have evaluated the contribution of the sympathetic nervous system to the hyperalgesia induced by bradykinin, a preferential B2-receptor agonist, and des-Arg9-bradykinin, a major metabolite of bradykinin and a selective B1-receptor agonist. Mechanical hyperalgesia was quantified by the Randall-Selitto paw-withdrawal method. Inflammation was induced by injecting Complete Freunds Adjuvant into the left hindpaw of the rat and testing mechanical nociceptive threshold in the right hindpaw after injecting B1 or B2 agonists and/or antagonists. Sympathectomy was achieved by surgically removing sympathetic ganglia L1-L4. Rats were used 48 h post-adjuvant injection. In the normal rat, intradermal injection of bradykinin but not des-Arg9-bradykinin, into the dorsal surface of the hindpaw, produced a dose-dependent decrease in mechanical nociceptive threshold. NPC 17731, a B2-receptor antagonist, but not des-Arg9-[Leu8]-bradykinin, a B1-receptor antagonist, almost completely inhibited the decrease in mechanical threshold, suggesting that bradykinin hyperalgesia in the normal rat hindpaw was mediated by B2 receptors. In rats whose left paws were treated, 48 h earlier, with adjuvant, intradermal injection of bradykinin or des-Arg9-bradykinin, into the right paw produced dose-dependent hyperalgesia. Bradykinin hyperalgesia was partially inhibited by NPC 17731, and the residual part by des-Arg9,[Leu8]-bradykinin. des-Arg9-bradykinin hyperalgesia was inhibited by des-Arg9,[Leu8]-bradykinin but not by NPC17731. These results suggest that in the setting of inflammation, bradykinin hyperalgesia was mediated by both B1 and B2 receptors, and that des-Arg9-bradykinin hyperalgesia was mediated by the B1 receptor. Forty-eight hours after injection of complete Freunds adjuvant, in sympathectomized rats, bradykinin or des-Arg9-bradykinin failed to produce hyperalgesia, suggesting that intact sympathetic postganglionic neurons are required for the hyperalgesia produced by these agents in this model. These results are consistent with the suggestions that B2 receptors mediate bradykinin-induced cutaneous hyperalgesia in the normal rat hindpaw. The hyperalgesia induced by bradykinin, 48 h post injection of complete Freunds adjuvant is mediated by both B1 and B2 receptors, that by des-Arg9-bradykinin is mediated by B1 receptors. The hyperalgesia induced by both agents is dependent on the presence of intact sympathetic postganglionic neurons.

Vagal branches involved in inhibition of bradykinin‐induced synovial plasma extravasation by intrathecal nicotine and noxious stimulation in the rat.

1. Stimulation of cutaneous and spinal visceral nociceptive afferents and intrathecal nicotine reduces bradykinin‐induced plasma extravasation (BK‐induced PE) in the knee joint of the rat. This depression is mediated by the hypothalamo‐pituitary‐adrenal (HPA) axis and is potentiated by subdiaphragmatic vagotomy. It is believed that activity in vagal afferents tonically inhibits ascending impulse transmission in the neuraxis projecting to the hypothalamus. Vagotomy, by removing such inhibition, allows greater depression of BK‐induced PE. In this study we determined whether the vagal afferents which negatively regulate activities of the HPA axis are present in all branches of the abdominal vagus nerves or only in specific branches. 2. We measured the depression of BK‐induced PE elicited by graded stimulation of spinal visceral afferents with intraperitoneal capsaicin and by intrathecal nicotine in vagus‐intact rats and in rats in which specific vagal branches were selectively interrupted. (i) Interruption of the coeliac branches mimicked the effect of total subdiaphragmatic vagotomy in potentiating the depression of BK‐induced PE generated by intrathecal nicotine and by stimulation of spinal visceral afferents. (ii) Interruption of the gastric and hepatic branches of the abdominal vagus nerves together or individually did not affect the depression of BK‐induced PE generated by the two stimuli. 3. These results indicate that afferent activity in coeliac and accessory coeliac vagal branches is involved in the regulation of the nociceptive system‐initiated depression of BK‐induced PE. The afferent fibres in these vagal branches involved probably monitor physiological events in abdominal visceral organs.

Sympathetic-dependence in bradykinin-induced synovial plasma extravasation is dose-related

While previous studies have implicated a role for sympathetic postganglionic neuron-terminals in bradykinin-induced plasma extravasation, a recent report by Cambridge and Brain [Br. J. Pharmacol., 115 (1995) 641-647] has suggested that it is sympathetic-independent. However, the doses of bradykinin used in these two groups of studies were considerably different. Therefore, in the present study, we characterized the sympathetic-dependence of plasma extravasation at varying doses of bradykinin. By measuring the concentration of Evans blue dye extravasation into the joint perfusate following its intravenous injection, bradykinin-induced plasma extravasation in the knee joint cavity was determined spectrophotometrically. To examine the role of sympathetic postganglionic neuron terminals in mediating bradykinin-induced plasma extravasation, we used surgical ablation of the lumbar sympathetic chain. Intra-articular perfusion of BK dose-dependently increased synovial plasma extravasation. After surgical sympathectomy, the dose-response curve for bradykinin-induced plasma extravasation was significantly shifted to the right. We conclude that at concentrations observed in inflamed tissues (between 10(-8) and 10(-7) M), bradykinin-induced plasma extravasation is largely mediated by sympathetic postganglionic neuron terminals.

Central terminals of nociceptors are targets for nicotine suppression of inflammation

Spinal intrathecal administration of nicotine inhibits bradykinin-induced plasma extravasation, a component of the inflammatory response, in the knee joint of the rat in a dose-related fashion. Nociceptors contain nicotinic receptors and activation of a nociceptor at its peripheral terminal, by capsaicin, also produces inhibition of inflammation. Therefore the aim of this study was to test the hypothesis that the spinal target for this effect of nicotine is the central terminal of the primary afferent nociceptor. Intrathecal administration of the neurokinin-1 receptor antagonist, (3aR,7aR)-7,7-diphenyl-2-(1-imino-2(2-methoxyphenyl)-ethyl) perhydroisoindol-4-1 hydrochloride or the N-methyl-D-aspartate receptor antagonist, DL-2-amino-5-phosphonovaleric acid, both antagonists of the action of primary afferent neurotransmitters, markedly attenuated the inhibition of bradykinin-induced plasma extravasation produced by both intrathecal nicotine and intraplantar capsaicin.Conversely, intrathecal administration of an alpha-adrenoceptor antagonist, phentolamine or an opioid receptor antagonist, naloxone, to block descending antinociceptive controls, which provide inhibitory input to primary afferent nociceptors, enhanced the action of both nicotine and capsaicin. These findings support the hypothesis that the central terminal of the primary afferent nociceptor is a CNS target at which nicotine acts to inhibit inflammation.

Spino‐bulbo‐spinal pathway mediating vagal modulation of nociceptive‐neuroendocrine control of inflammation in the rat

1 Stimulation of nociceptors by intradermal capsaicin produces depression of bradykinin (BK)‐induced synovial plasma extravasation (PE) that is markedly enhanced by subdiaphragmatic vagotomy. This depression is mediated by the adrenal medullae, a propriospinal pathway between the afferent nociceptive input and preganglionic neurones projecting to the adrenal medullae, and a spino‐bulbo‐spinal pathway. Here we investigated the role of spinal ascending and descending pathways in the interaction between noxious and vagal afferent inputs, leading to inhibition of BK‐induced PE mediated by the adrenal medullae. Nociceptors in the paw were activated by capsaicin and depression of BK‐induced PE was measured in rats with intact or cut subdiaphragmatic vagus nerves. 2 After cutting the dorsolateral funiculus (DLF) contralateral to the stimulated hindpaw (segmental level C5/C6 and T8/T9), depression of BK‐induced PE was weak or absent both in rats with intact vagus nerves and in vagotomised rats, suggesting that an ascending excitatory pathway was interrupted. 3 After cutting the DLF ipsilateral to the stimulated hindpaw, depression of BK‐induced PE was already markedly enhanced, even in the absence of vagotomy. Ipsilateral DLF lesion (L2/L3) below the level of the spinal output to the adrenal medullae produced the same effect, suggesting interruption of a descending inhibitory pathway that relays the effect of vagal activity to the level of the capsaicin‐induced nociceptive input. 4 Contralateral and ipsilateral hemisection of the spinal cord (C5/C6) produced the same changes as the corresponding DLF lesions. 5 Ipsi‐ or contralateral lesion of the dorsal funiculus at the spinal level T8/T9 had no effect on depression of BK‐induced PE generated by cutaneous noxious stimulation of the forepaw. 6 We suggest that noxious stimulation activates an ascending pathway of the spino‐bulbo‐spinal excitatory circuit which projects through the DLF contralateral to the nociceptive input, and that the inhibitory pathway which is activated by vagal afferent activity projects through the DLF ipsilateral to the nociceptive input.

Nociceptive neuroendocrine negative feedback control of neurogenic inflammation activated by capsaicin in the rat paw: role of the adrenal medulla

1 Recently we have found that inhibition of bradykinin‐induced synovial plasma extravasation by transcutaneous electrical stimulation at strengths which excite unmyelinated afferent axons is mediated by the hypothalamo‐pituitary‐adrenal axis. 2 Here we tested whether stimulation of nociceptors in the rat paw by intradermally injected capsaicin inhibits bradykinin‐induced synovial plasma extravasation and whether this inhibition is mediated by the hypothalamo‐pituitary‐adrenal or sympatho‐adrenal axis. Furthermore, we tested whether inhibition of bradykinin‐induced plasma extravasation generated by intraperitoneally injected capsaicin, which preferentially excites visceral afferents, is mediated by the hypothalamo‐pituitary‐adrenal or sympatho‐adrenal axis. We used normal rats, subdiaphragmatically vagotomized rats, rats with denervated adrenal medullae and rats with acutely transected spinal cords at the segmental levels T1/T2 or T12/L1. 3 Injection of capsaicin into the plantar or palmar surface of the paws produced a depression of bradykinin‐induced plasma extravasation. The inhibition elicited from the forepaw was larger than that from the hindpaw. 4 The inhibition of bradykinin‐induced plasma extravasation elicited from both paws was potentiated by subdiaphragmatic vagotomy. 5 Denervation of the adrenal medullae abolished the inhibitory effect of intradermal capsaicin in vagus‐intact and in vagotomized animals. 6 After spinalization at the segmental level T1/T2, capsaicin injected into the forepaw did not depress bradykinin‐induced plasma extravasation either in vagus‐intact or in vagotomized animals. Capsaicin injected into the hindpaw in these spinalized animals produced a small depression. After spinalization at the segmental level T12/L1 no depression was produced by capsaicin injected into the hindpaw. 7 Depression of bradykinin‐induced plasma extravasation generated by intraperitoneal injection of capsaicin in vagus‐intact and in vagotomized animals was also abolished or attenuated after denervation of the adrenal medullae. This shows that this depression was also largely dependent on the activation of the sympatho‐adrenal system. 8 We conclude that depression of bradykinin‐induced plasma extravasation during stimulation of nociceptors by capsaicin is mediated predominantly by the sympathoadrenal pathway. This finding differs from the inhibitory mechanism of depression of bradykinin‐induced plasma extravasation generated by cutaneous electrical stimulation, which is mediated by the hypothalamo‐pituitary‐adrenal axis.

Role of adrenal medulla in development of sexual dimorphism in inflammation

Many inflammatory diseases show a female predilection in adults, but not prepubertally. Because sex differences in the inflammatory response in the adult rat are mediated, in part, by sexual dimorphism in adrenal medullary function, we investigated the contribution of the adrenal medulla to the ontogeny of sexual dimorphism in inflammation. Whilst there was no sex difference in the magnitude of the plasma extravasation (PE) induced by the potent inflammatory mediator bradykinin (BK) in prepubertal rats, in adult rats BK‐induced PE was markedly greater in males. Also, adult male rats, gonadectomized prior to puberty, had a lower magnitude of BK‐induced PE than did adult male controls, whilst adult females gonadectomized prepubertally had higher BK‐induced PE than did controls. In rats gonadectomized after puberty, the magnitude of BK‐induced PE in adult males was not affected, whilst in females it resulted in significantly higher BK‐induced PE, similar to the effect of prepubertal gonadectomy. When tested prepubertally, adrenal denervation increased the magnitude of BK‐induced PE in females, but not in males. In contrast, in both males and females tested as adults, but castrated prepubertally, and in gonad‐intact adult females, adrenal denervation significantly increased the magnitude of BK‐induced PE. Adrenal denervation in prepubertal females given adult levels of 17β‐oestradiol produced a marked enhancement in the denervation‐induced increase in magnitude of BK‐induced PE compared to females not exposed prematurely to sex hormones. These studies suggest that an adrenal medulla‐dependent inhibition of BK‐induced PE is present in female but not male rats, and is enhanced by oestrogen but suppressed by testosterone.