The Adrenal Medulla Modulates Mechanical Allodynia in a Rat Model of Neuropathic Pain.

We have investigated whether the stress response mediated by the adrenal medulla in rats subjected to chronic constriction injury of the sciatic nerve (CCI) modulates their nocifensive behavior. Treatment with SK29661 (300 mg/kg; intraperitoneal (I.P.)), a selective inhibitor of phenylethanolamine N-methyltransferase (PNMT) that converts noradrenaline (NA) into adrenaline (A), fully reverted mechanical allodynia in the injured hind paw without affecting mechanical sensitivity in the contralateral paw. The effect was fast and reversible and was associated with a decrease in the A to NA ratio (A/NA) in the adrenal gland and circulating blood, an A/NA that was elevated by CCI. 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (SKF29661) did not affect exocytosis evoked by Ca2+ entry as well as major ionic conductances (voltage-gated Na+, Ca2+, and K+ channels, nicotinic acetylcholine receptors) involved in stimulus-secretion coupling in chromaffin cells, suggesting that it acted by changing the relative content of the two adrenal catecholamines. Denervation of the adrenal medulla by surgical splanchnectomy attenuated mechanical allodynia in neuropathic animals, hence confirming the involvement of the adrenal medulla in the pathophysiology of the CCI model. Inhibition of PNMT appears to be an effective and probably safe way to modulate adrenal medulla activity and, in turn, to alleviate pain secondary to the injury of a peripheral nerve.

Overexpression of P2X3 and P2X7 Receptors and TRPV1 Channels in Adrenomedullary Chromaffin Cells in a Rat Model of Neuropathic Pain.

We have tested the hypothesis that neuropathic pain acting as a stressor drives functional plasticity in the sympathoadrenal system. The relation between neuropathic pain and adrenal medulla function was studied with behavioral, immunohistochemical and electrophysiological techniques in rats subjected to chronic constriction injury of the sciatic nerve. In slices of the adrenal gland from neuropathic animals, we have evidenced increased cholinergic innervation and spontaneous synaptic activity at the splanchnic nerve⁻chromaffin cell junction. Likewise, adrenomedullary chromaffin cells displayed enlarged acetylcholine-evoked currents with greater sensitivity to α-conotoxin RgIA, a selective blocker of α9 subunit-containing nicotinic acetylcholine receptors, as well as increased exocytosis triggered by voltage-activated Ca2+ entry. Altogether, these adaptations are expected to facilitate catecholamine output into the bloodstream. Last, but most intriguing, functional and immunohistochemical data indicate that P2X3 and P2X7 purinergic receptors and transient receptor potential vanilloid-1 (TRPV1) channels are overexpressed in chromaffin cells from neuropathic animals. These latter observations are reminiscent of molecular changes characteristic of peripheral sensitization of nociceptors following the lesion of a peripheral nerve, and suggest that similar phenomena can occur in other tissues, potentially contributing to behavioral manifestations of neuropathic pain.

Assessment of circulating concentrations of proinflammatory and anti-inflammatory cytokines and nitric oxide in dogs with brachycephalic airway obstruction syndrome.

OBJECTIVE: To evaluate plasma concentrations of inflammatory mediators in dogs with brachycephalic airway obstruction syndrome, identify a possible role for these mediators in the syndrome, and investigate the relationship between plasma concentrations of inflammatory mediators and severity of clinical signs. ANIMALS: 17 dogs with brachycephalic airway obstruction syndrome and 10 mesocephalic (control) dogs. PROCEDURES: A blood sample was collected once from each dog. Plasma concentrations of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, IL-17A, IL-10, and IL-13 were measured with ELISAs. Nitric oxide (NO) concentrations were determined with a Griess test. For analysis, brachycephalic dogs were categorized into groups depending on weight (small [< 16 kg]) and large [≥ 16 kg]) or on whether they required medical or surgical treatment. RESULTS: Compared with control dog values, plasma concentrations of TNF-α, IL-10, IL-13, and IL-17A were significantly higher in brachycephalic dogs and markedly so for brachycephalic dogs that required surgery; findings for small and large brachycephalic dogs did not differ. A similar pattern of differences between control and brachycephalic dogs was identified for plasma NO concentration. Plasma IL-1ß and IL-6 concentrations in control and brachycephalic dogs did not differ. CONCLUSIONS AND CLINICAL RELEVANCE: In brachycephalic dogs, plasma TNF-α, IL-10, IL-13, L-17A, and NO concentrations were higher than values in control dogs and appeared to be associated with disease severity. These variables may be useful as indicators of inflammatory processes associated with brachycephalic airway obstruction syndrome in dogs.