Nitric oxide evokes pain at nociceptors of the paravascular tissue and veins in humans.

Abstract

1. Nitric oxide (NO) evokes pain on intracutaneous application, apparently by exciting cutaneous nociceptors. To look for similarities in the responsiveness and sensitivity of other nociceptive systems to NO we determined pain intensity-concentration relations for NO applied to paravascular tissue and veins in humans. 2. NO solutions (0O4-2-0 mM) were either injected paravascularly or perfused through a vascularly isolated hand vein segment. The subjects rated pain continuously with the help of an electronically controlled visual analog scale, which made it possible to determine both the time course (latency, duration) and the intensity of NO-evoked pain. 3. Regardless of where it was applied, at concentrations above 07 mm NO always evoked pain of similar time course and concentration dependence. Pain increased proportionally to the concentration of applied NO, reaching subjects' tolerance maximum at four to five times the threshold concentration. 4. Pain intensity-NO concentration relations were congruent, indicating that the respective nociceptive systems are equally sensitive to NO. 5. Our observations are consistent with the hypothesis that NO is a chemical link in peripheral nociception.Nitric oxide (NO), perhaps a chemical link in nociception (Meller & Gebhardt, 1993), evokes pain on intracutaneous injection in humans, probably by exciting cutaneous nociceptors (Holthusen & Arndt, 1994). The question, therefore, arises whether it has a similar effect on other nociceptive systems, in particular those of blood vessels and that of the paravascular tissue, which is believed to convey visceral pain (Lim, Liu, Guzman & Braun, 1962

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…Pain induced by bradykinin injected into a vascularly isolated vein segment in humans was reduced by inhibition of NOS or GC, pointing to an involvement of NO and cGMP in the algogenic action of bradykinin in this model (291,364). Consistent with this, exogenously applied NO solutions also induced pain in this experimental arrangement (289). The reflex increase in renal sympathetic nerve activity induced by epicardial application of bradykinin was reduced by systemic NOS inhibition in dogs (765).…”

“…In accord, aqueous NO solutions either injected intracutaneously, paravascularly, or perfused through a vascularly isolated hand vein segment in humans evoked overt pain in a concentration-dependent manner; no hyperalgesia, edema, or inflammation was reported to result from these experiments (289,290). Exogenous NO delivered as a locally applied NO precursor or NO donor induced mechanical hyperalgesia in rats that was diminished by inhibition of GC (15,361).…”

Molecular characterization of TRPA1 channel activation by cysteine-reactive inflammatory mediators

“…21,22 NO is a short-lived mediator whose release is strongly potentiated mainly by inducible NO synthase (NOS) in inflammation. 23,24 The non-selective NOS inhibitor, N ω -nitro-Larginine methyl ester, reduces thermal hyperalgesia in inflammatory pain models, 25 and intracutaneous injections of NO precursors evoke pain in humans, 26 indicating a role of NO in inflammatory pain. Likewise, it is known that a large amount of H 2 O 2 exist at inflamed sites.…”

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“…NO play important role in nociception 124 . It causes pain when injected into the skin of human subjects 125 and contributes to peripheral hyperalgesia in the skin and joints, probably by contributing to PGE2-induced sensitization of primary afferents 126 .…”