Sympathetic Modulation of Activity in Aδ- and C-Primary Nociceptive Afferents After Intradermal Injection of Capsaicin in Rats

Abstract

Neuropathic and inflammatory pain can be modulated by the sympathetic nervous system. In some pain models, sympathetic postganglionic efferents are involved in the modulation of nociceptive transmission in the periphery. The purpose of this study is to examine the sensitization of Adelta- and C-primary afferent nociceptors induced by intradermal injection of capsaicin (CAP) to see whether the presence of sympathetic efferents is essential for the sensitization. Single primary afferent discharges were recorded from the tibial nerve after the fiber types were identified by conduction velocity in anesthetized rats. An enhanced response of some Adelta- and most C-primary afferent fibers to mechanical stimuli was seen in sham-sympathectomized rats after CAP (1%, 15 mul) injection, but the enhanced responses of both Adelta- and C-fibers were reduced after sympathetic postganglionic efferents were removed. Peripheral pretreatment with norepinephrine by intraarterial injection could restore and prolong the CAP-induced enhancement of responses under sympathectomized conditions. In sympathetically intact rats, pretreatment with an alpha(1)-adrenergic receptor antagonist (terazosin) blocked completely the enhanced responses of C-fibers after CAP injection in sympathetically intact rats without significantly affecting the enhanced responses of Adelta-fibers. In contrast, a blockade of alpha(2)-adrenergic receptors by yohimbine only slightly reduced the CAP-evoked enhancement of responses. We conclude that the presence of sympathetic efferents is essential for the CAP-induced sensitization of Adelta- and C-primary afferent fibers to mechanical stimuli and that alpha(1)-adrenergic receptors play a major role in the sympathetic modulation of C-nociceptor sensitivity in the periphery.

Involvement of Peripheral Purinoceptors in Sympathetic Modulation of Capsaicin-Induced Sensitization of Primary Afferent Fibers

“…In a series of recent studies, we demonstrated in anesthetized rats that sensitization of primary afferent nociceptors and the cutaneous neurogenic inflammation arising from activation of the transient receptor potential vanilloid-1 (TRPV 1 ) receptors by intradermal injection of capsaicin (CAP) are dependent on the presence of sympathetic efferents and are subject to modulation by peripheral ␣ 1 -adrenoceptors (Lin et al 2003;Ren et al 2005a) and NPY Y 2 receptors ). The present investigation is a continuation of our series of studies and is aimed at further examination of the possible involvement of peripheral P2X and P2Y receptors in the sympathetically modulated sensitization of primary A␦-and C-nociceptive afferents produced by intradermal injection of CAP in anesthetized rats.…”

Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

“…For example, in uninjured rats blockade of  1 -adrenoceptors inhibited behavioural signs of pain induced by subcutaneous injection of the  1 -adrenoceptor agonist phenylephrine and β-methylene-ATP (an agonist for purinergic P2X3 receptors) (Meisner et al, 2007), whereas blockade of  2 -adrenoceptors was ineffective. Similarly, blockade of  1 -but not  2 -adrenoceptors abolished hyperalgesia and C-fibre discharge evoked by intradermal injection of capsaicin (Kinnman and Levine;1995;Ren et al, 2005). In studies on healthy humans, intradermal injection of  1 -and  2 -adrenergic agonists increased sensitivity to heat-pain (Fuchs et al, 2001), as did iontophoresis of noradrenaline and phenylephrine in mildly burnt or inflamed skin (Drummond, 1995;Drummond, 1998;Drummond, 2009a).…”

Involvement of Selective Alpha-2 Adrenoreceptor in Sympathetically Maintained Pain

“…The intravenous administration of the nonspecific alpha-blocker phentolamine can result in similar pain relief as that of blockade of the sympathetic ganglion 16) . Hence, it was presumed that alpha-1 AR play a major role in the SMP 13,17) . However, in an animal model 19) following nerve injury, there appears to be an increase in alpha-2 like AR sites at peripheral sensory neurons and cutaneous nociceptor in rabbit become sensitive to adrenergic agonist.…”