Joachim O. Arndt

Nitric oxide evokes pain in humans on intracutaneous injection

To test the hypothesis that nitric oxide (NO) acts algetically in humans, we determined pain intensity/dose relations for intracutaneously applied NO solutions. NO, dissolved in isoosmolar phosphate buffer, was injected in the forearm of six volunteers and the subjects rated NO-evoked pain continuously with the help of an electronically controlled visual analogue scale. Pain always occurred at a NO dose of 12 nmol, increased with dose and reached the tolerance maximum at 50 nmol. This shows for the first time the genuine pain evoking properties of NO.

Subjective Ratings of Pain Correlate with Subcortical-Limbic Blood Flow: An fMRI Study

Studies investigating the cerebral representations of pain using functional imaging techniques failed to elucidate the affective aspects of pain. This investigation used functional magnetic resonance imaging to measure pain-related changes in cerebral activity during painful stimulation with a strong affective component. Vascular pain was induced via balloon dilatation of a dorsal foot vein of healthy volunteers. The subjects rated their perceived pain uninterruptedly during imaging, allowing cerebral activity to be correlated with both stimulus function (boxcar) and, more importantly, subjective ratings reflecting individual pain experience. The findings indicated signal increases in subcortical-limbic regions, particularly in the amygdala. This region is suggested to be involved in the affective dimension of pain.

The nociceptive systems of skin, paravascular tissue and hand veins of humans and their sensitivity to bradykinin

To study the pain-evoking properties of bradykinn on the nociceptive systems of skin, paravascular tissue and hand veins of humans, bradykinin was injected intracutaneously, retrogradially into occluded finger veins for reaching the paravascular tissue or into vascularly isolated hand vein segments of seven subjects. Regardless of the injection site, bradykinin always evoked pain of concentration-related intensity within nearly similar concentration ranges of 0.1-10.0 microM, yielding congruent pain intensity-concentration relations. Thus, in humans, the nociceptive systems of skin, deep tissue and hand veins are equally sensitive to the endogenous algetic bradykinin.

Nitric oxide as a chemical link in the generation of pain from veins in humans

&NA; In humans, both nitric oxide (NO) and bradykinin, a naturally occurring algetic and a potent NO liberator, evoke pain from hand veins. The afferent innervation of these veins consists solely of polymodal nociceptors which are located close to the endothelium, a well‐known source of NO, thus suggesting NO as a chemical link in nociception. Consistent with this hypothesis, our observations show that neither bradykinin, nor hyperosmolar solutions (a noxious physicochemical stimulus) evoke pain from hand vein segments that have been exposed to the NO‐synthase (NOS) inhibitor NG‐mono‐methyl‐L‐arginine. An intact NOS pathway is therefore a prerequisite for pain to toe evoked by bradykinin and hyperosmolar solutions from veins, indicating for the first time in humans that vascular pain is mediated by NO. Thus, new directions for research on analgesics may be opened.

Endogenous Vasopressin Supports Blood Pressure and Prevents Severe Hypotension during Epidural Anesthesia in Conscious Dogs

To evaluate whether, and to what extent, release of endogenous vasopressin supports blood pressure when efferent sympathetic drive is blocked by epidural anesthesia, the authors studied the effects of high epidural anesthesia alone and when vasopressin was prevented from acting at its vascular (V1)-receptor in six awake, trained, unsedated dogs. On different days, the same dose of 0.5% bupivacaine (8-13 ml) was injected epidurally in a randomized fashion either in the presence or absence of (V1)-vasopressin receptor blockade, and the effects were evaluated on cardiovascular (arterial blood pressure, heart rate) and respiratory (blood gases, oxygen consumption) variables, and on plasma concentrations of vasopressin and renin. Results were also contrasted to those obtained after epidural injection of saline alone (placebo) in the same dogs. When endogenous vasopressin was prevented from acting by intravenous pretreatment with a specific V1-receptor antagonist (beta-mercapto-beta, beta-cyclopenta-methylene-propionyl-O-Me-Tyr-Arg-Vasopressin), epidural anesthesia resulted in a rapid and sustained 35% decrease in mean arterial blood pressure from 92 mmHg +/- 5 SE to 60 mmHg +/- 4. In contrast, only a 14% decrease in mean blood pressure from 92 mmHg +/- 5 to 79 mm Hg +/- 6 was noted after epidural anesthesia alone. This difference between groups was statistically significant (P = 0.0001). The V1-receptor blockade alone had no detectable effect. Vasopressin plasma concentrations significantly increased from 3.4 +/- 0.3 pg.ml-1 to 16.2 +/- 3.2 pg.ml-1 after epidural anesthesia but did not change after epidural saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic Blockade by Epidural Anesthesia Attenuates the Cardiovascular Response to Severe Hypoxemia

Blood pressure is usually well maintained during epidural or spinal anesthesia even in the presence of extensive sympathetic blockade. The authors investigated whether hormonal systems support arterial pressure and how the circulation copes with a hypoxic challenge when activation of the sympathetic nervous system is selectively impaired by neural blockade. Accordingly, the effects of high epidural anesthesia alone and combined with hypoxia were evaluated in seven awake trained dogs. On different days, either bupivacaine 0.5% (8-12 ml) or saline (placebo) were randomly injected epidurally and the effects evaluated on cardiovascular (arterial pressure, heart rate) and respiratory (blood gases, oxygen consumption) variables, as well as on hormone plasma concentrations (vasopressin, norepinephrine, epinephrine, renin) during both normoxia and hypoxia. During epidural anesthesia alone, vasopressin increased tenfold (1.7 pg/ml +/- 1.0 SD to 16.8 +/- 13.8, P less than 0.05), norepinephrine decreased (90 pg/ml +/- 31 to 61 +/- 28, P less than 0.05) while epinephrine and renin concentrations remained unchanged. Mean arterial and pulse pressure decreased by 13 mmHg and 23 mmHg (P less than 0.05), respectively. In dogs without sympathetic blockade (saline group), hypoxemia (PaO2: 31 +/- 4 mmHg) evoked an increase in mean blood pressure by 37 mmHg +/- 8 and heart rate by 50 beats per min +/- 17. In contrast, in the presence of sympathetic blockade but with a similar degree of hypoxemia, blood pressure failed to increase (+ 1 mmHg +/- 14) and heart rate rose by only 15 beats per min +/- 11. These differences between groups were statistically significant (P less than 0.001). Hypoxemia induced a similar hypocarbia (PaCO2:25 mmHg) in both groups, indicating that the ventilatory response to hypoxemia was preserved after epidural blockade. During hypoxemia vasopressin concentrations increased 35-fold to 64 pg/ml +/- 38 (P less than 0.0001) compared to base line only during epidural anesthesia, but not after epidural saline (2 pg/ml +/- 2), while other hormones showed no significant differences. The authors conclude that high epidural anesthesia in awake unsedated dogs: 1) almost completely abolishes the normal cardiovascular response to hypoxemia while promoting vasopressin secretion; 2) preserves the ventilatory response to hypoxemia; and 3) is associated with increased vasopressin concentrations, most likely to compensate for decreased cardiac filling and/or arterial blood pressure when sympathoadrenal responses are impaired. Thus, the changes in cardiovascular vital signs in response to severe hypoxemia are markedly blunted when spinal sympathetic outflow is selectively eliminated by epidural anesthesia.

Pain but no temperature sensations are evoked by thermal stimulation of cutaneous veins in man

To test the hypothesis that the sensory innervation of veins subserves nociception exclusively, we studied pain and temperature sensations on intravenously applied thermal stimuli before and after blockade of either cutaneous or venous afferents in man. Intravenous cooling or warming of a cutaneous vein segment of the hand was associated with corresponding changes in skin temperature and evoked pain only after numbing the skin but temperatures sensations only after intravenous local anesthesia. Thus, the sensory elements of veins, probably polymodal nociceptors, convey pain only on thermal stimulation while coactivated cutaneous thermoreceptors are responsible for concomitant temperature sensations.

Tachyphylaxis to Local Anesthetics Does Not Result from Reduced Drug Effectiveness at the Nerve Itself

Possible development of tachyphylaxis to local anesthetics in the nerve itself (time-dependent change in axonal conduction properties) was studied in the aortic nerve of eight rabbits anesthetized with urethane. The nerve was immersed in Tyrode solution with or without bupivacaine at pH 7.4 and 38 degrees C in a trough molded from the surrounding tissues. After control measurements the nerve was exposed to increasing bupivacaine concentrations until complete nerve block at minimal blocking concentration. Subsequently, bupivacaine concentrations were reduced and kept constant for 4 h (partial block). Finally, intact nerve function was confirmed after bupivacaine washout with Tyrode solution. For quantification total nerve activity was recorded continuously and related to drug concentrations. Two findings argue against the occurrence of tachyphylaxis at the nerve itself: 1) nerve activity decreased rather than increased over time in the presence of constant bupivacaine concentrations during partial block; and 2) for the same bupivacaine concentration, nerve activity during partial block was always lower than during the initial blocking experiments. Thus, drug effectiveness increased rather than decreased over time, which cannot be reconciled with the theory that tachyphylaxis might be mediated by changes in axonal conduction properties.

The role of pain from veins for the formation of perivenous edema in humans

&NA; To test the hypothesis that nociception from veins plays a role in the formation of perivenous edema, we looked at edema along hand veins of humans during painful noxious stimulation in the presence and absence of nerve conduction block. Pain from vascularly isolated hand vein segments was evoked by perfusion with hyperosmolar saline and rated with the help of an electronically controlled visual analogue scale. Perivenous edema measured as changes in skin altitude was continuously recorded by means of infrared reflection. To alternately block the innervation of skin and vein segment we used a perivenous block (vein but not skin numbed), a distal ulnar nerve block (skin but not vein numbed), and a proximal ulnar nerve block (both vein and skin numbed). Without nerve block, hyperosmolar saline always evoked both pain and a continuous increase in perivenous edema to a maximum of 2.0–3.2 mm after 30 min. On painless control perfusions with isoosmolar saline, edema increased slightly (0.2–0.8 mm) to a plateau which was maintained until the end of perfusion. When the vein was denervated by perivenous or proximal ulnar nerve block, hyperosmolar saline evoked a slight increase in edema which resembled that of control perfusions in both extent and time course. On distal ulnar nerve block, which numbed the skin but not the vein, both pain and substantial edema were evoked. These observations show that nociception from veins is a prerequisite for perivenous edema to occur.

Nalbuphine does not act analgetically in electrical painful tooth pulp stimulation in man

&NA; Nalbuphine is a mixed opioid agonist/antagonist, the analgesic properties of which are still open to debate. In a randomized and placebo‐controlled protocol, we compared its effects (0.2 mg/kg) on mans perception of multimodal stimuli (i.e., nociceptive, acoustic and visual) to those of aspirin (acetylsalicylic acid, 10 mg/kg) and meperidine (0.5 mg/kg). Amplitudes and latencies of the evoked potentials (EP), tolerance maxima to painful tooth pulp stimuli, and subjective intensity ratings were measured as indicators of drug induced perception differences. After nalbuphine, the EP amplitudes markedly decreased while the stimuli of each modality were rated by the subjects to be of higher intensity. Also, the tolerance maxima of painful tooth pulp stimulation were reduced by nalbuphine, and naloxone did not have additional effects. In contrast, after aspirin and meperidine, the subjective pain ratings corresponded to the reduction of nociceptive EP amplitudes. Tolerance maxima to painful stimulation were also increased by both drugs. While aspirin did not influence acoustic and visual perception, meperidine caused a slight increase in EP amplitudes as well as in the intensity ratings of these stimuli relative to placebo. Thus, at the dose studied, nalbuphine did not act analgetically. The amplitude reduction of nociceptive EP suggested that nalbuphine had analgetic properties. These were, however, not confirmed by subjective pain ratings nor by changes in tolerance maxima.