Multiple impairments of cutaneous nociceptor function induced by cardiotoxic doses of Adriamycin in the rat

Abstract

Besides their deleterious action on cardiac muscle, anthracycline-type cytostatic agents exert significant neurotoxic effects on primary sensory neurons. Since cardiac sensory nerves confer protective effects on heart muscle and share common traits with cutaneous chemosensitive nerves, this study examined the effects of cardiotoxic doses of adriamycin on the function and morphology of epidermal nerves. Sensory neurogenic vasodilatation, plasma extravasation, and the neural CGRP release evoked by TRPV1 and TRPA1 agonists in vitro were examined by using laser Doppler flowmetry, the Evans blue technique, and ELISA, respectively. Carrageenan-induced hyperalgesia was assessed with the Hargreaves method. Immunohistochemistry was utilized to study cutaneous innervation. Adriamycin treatment resulted in profound reductions in the cutaneous neurogenic sensory vasodilatation and plasma extravasation evoked by the TRPV1 and TRPA1 agonists capsaicin and mustard oil, respectively. The in vitro capsaicin-, but not high potassium-evoked neural release of the major sensory neuropeptide, CGRP, was markedly attenuated after adriamycin treatment. Carrageenan-induced inflammatory hyperalgesia was largely abolished following the administration of adriamycin. Immunohistochemistry revealed a substantial loss of epidermal TRPV1-expressing nociceptive nerves and a marked thinning of the epidermis. These findings indicate impairments in the functions of TRPV1 and TRPA1 receptors expressed on cutaneous chemosensitive nociceptive nerves and the loss of epidermal axons following the administration of cardiotoxic doses of adriamycin. Monitoring of the cutaneous nociceptor function in the course of adriamycin therapy may well be of predictive value for early detection of the deterioration of cardiac nerves which confer protection against the deleterious effects of the drug.

Capsaicin‐induced rapid neutrophil leukocyte activation in the rat urinary bladder microcirculatory bed

“…An early increase in the frequency of endothelial-PMN interactions (both rolling and adhesion) was observed in the bladder postcapillary venules as early as 15 min after the administration of capsaicin and these inflammatory changes persisted throughout the entire experimental period (45 min). The early onset of inflammatory changes following capsaicin administration is in line with previous observations that found a rapid development of NK1 receptor-dependent edema formation and PMN deposition after capsaicin in the skin 10 and in the pancreas, 14 and an even more rapid response occurring within minutes following an intratracheal administration of capsaicin. 19 We have also demonstrated that the microvascular changes were brought about via a specific action of capsaicin on sensory nerves expressing TRPV1 receptors, as capsaicininduced cellular inflammatory reactions were strongly inhibited by both TRPV1 receptor antagonism and the elimination of TRPV1-expressing nociceptive primary sensory neurons by neonatal capsaicin treatment.…”

“…TRPV1 activation is known to bring about characteristic microcirculatory reactions in several organs. The activation of the TRPV1 receptor, through the release of vasoactive peptides such as calcitonin gene related peptide (CGRP) and substance P (SP) from the sensory nerves, results in an extremely rapid elevation in blood flow and an increase in cutaneous and dural permeability . TRPV1‐mediated vasodilatory effects are partially linked to the release of CGRP in the dura mater and the skin .…”

“…This is supported by findings showing that the release of nitric oxide could be inhibited by pretreatment with the TRPV1 receptor antagonist capsazepine in vitro 12 and by sensory denervation in vivo. 13 Edema formation elicited by the activation of TRPV1 receptors, however, is linked to the release of SP and its binding to endothelial neurokinin-1 (NK1) receptors that lead to an increase in vascular permeability and polymorphonuclear leukocyte (PMN) infiltration, 10 where the dose-dependent increase in plasma extravasation evoked by SP and capsaicin could be inhibited by capsazepine 10,14 or by NK1 receptor antagonism. 3 Even though TRPV1 agonists are used in the therapeutic management of urinary bladder disorders, the potential acute microcirculatory side effects of TRPV1 activation have not yet been examined.…”

Phosphorylated Histone 3 at Serine 10 Identifies Activated Spinal Neurons and Contributes to the Development of Tissue Injury-Associated Pain

“…The great majority of nociceptive primary sensory neurons express the transient receptor potential cation channel sub-family V member 1 ion channel (TRPV1) that is pivotal in signalling, to the central nervous system, inflammatory events in peripheral tissues that quickly develop following burn injury20232425. Therefore, we studied the relationship of TRPV1-expressing spinal terminals of nociceptive primary sensory neurons and SSDHN exhibiting p -S10H3 expression in the nucleus (Fig.…”

“…Topical application or injection of capsaicin, the archetypal TRPV1 agonist25 induces, without producing tissue damage, an inflammatory response2425. The inflammatory response is accompanied by sensitisation of spinal dorsal horn neurons and subsequent development of prolonged pain28.…”