Intravesical capsaicin for neurogenic bladder dysfunction.
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Biomedical subjects
Publications and source records attributed to B Lynn.
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In anaesthetized rats, punctate pressure using forces greater than or equal to 20 mN caused small transient rises in skin blood flow that were similar in normally innervated and chronically denervated skin. A force of 11 mN, sufficient to excite most C-fibres of the polymodal nociceptor class, failed to cause vasodilatation. Following short periods of low frequency electrical stimulation of the saphenous nerve at C-fibre strength, larger increases in blood flow ('antidromic vasodilatation') were seen. Antidromic vasodilation was unaffected by high frequency stimulation of A alpha beta axons or by simultaneous innocuous mechanical stimulation. The failure of pressure at levels suprathreshold for C-fibre nociceptors to cause neurogenic vasodilatation may mean that antidromic vasodilation in rat skin is due to activity restricted to a mechanically insensitive sub-population of C-fibres.
1. Single applications of solutions of capsaicin were made to the intact skin of anaesthetized rats and the effects on cutaneous blood flow and the firing of C-nociceptor afferents determined. Blood flow was measured by laser-Doppler flowmetry. C-fibre activity was recorded from filaments dissected from the saphenous nerve. 2. Following the application of a capsaicin solution (concentration > or = 1 mM) to rat saphenous skin, low frequency firing occurred in C-polymodal nociceptors that sometimes continued for > 10 min. At the some time, large increases in skin blood flow occurred exceeding 300% in some instances. 3. After the initial excitation, some C-polymodal nociceptors lost their sensitivity to pressure whilst their sensitivity to heat was lost or enhanced depending on the vehicle used. 4. Sensitivity of C-polymodal nociceptors to heat recovered in < 1 day following a single application of 33 mM capsaicin. Thresholds to mechanical pressure, however, were still significantly elevated by 123% on day 1, but had recovered on day 2. 5. Vasodilatation in response to saphenous nerve stimulation ('antidromic vasodilatation') was significantly reduced by 35%, 2 days after a single application of 33 mM capsaicin, but was normal at 4 days. 6. Following a single application of 33 mM capsaicin, skin substance P levels fell to only half the normal value at day 1 and remained at this level throughout the 4 day period examined. 7. It is suggested that the ability of relatively low concentrations of capsaicin to desensitize C-fibre nociceptors may underlie the analgesic action of topical capsaicin in man.
We investigated whether flare crossed the mid-line in various positions in humans using laser Doppler flowmetry to confirm visual observations. On the back and forehead, flare crossed the mid-line. However, on the posterior part of the neck, flare did not cross the mid-line, an observation that may be related to the elongated shape of flare in this region.
Capsaicin selectively excites C-polymodal nociceptors in mammalian skin. In the rat, the only species so far studied in detail, a long-term desensitization of a subpopulation of C-polymodal nociceptors occurs after the initial excitation. After nerve treatment, permanent loss of some C-polymodal nociceptors is found in the rat. It is argued that capsaicin must act primarily on C fibres involved in signalling about pain and not itch, although there may be overlap between the C afferents involved in these two nociceptive sensations. The possibility is raised that C mechanoreceptors, with their good histamine sensitivity, are also involved in itch.
Flare was measured on the arm of human subjects at 8, 16, and 24 mm from localized areas of skin heating, using laser-Doppler flowmetry. Vasodilatation started after a delay that averaged 3.2 sec at 8 mm and increased significantly by 0.4 sec at 16 mm and by 1.1 sec at 24 mm. In contrast, there were no significant changes in onset delay associated with changes in the amplitude of the heat stimulus. Flare appears to spread more slowly than would be expected if rate of spread were determined only by conduction delays in unmyelinated nerve terminals. This finding is discussed in relation to models of flare that involve coupling between adjacent nerve terminals.
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The long-term effects of applying capsaicin briefly to a cutaneous nerve in the rabbit have been assessed 10 days after treatment. No changes in C-fibre numbers were seen in treated saphenous nerves and the average ratio of C-fibres to A-fibres was close to 7 in both control and treated nerves. However, the substance P content of the skin innervated by the saphenous nerve fell by 46% after capsaicin treatment compared with a fall of 65% after nerve section. Plasma extravasation in response to 7.5% mustard oil applied to the skin was also reduced following capsaicin treatment (by 43%) and following denervation (by 47%), although the response to 25% mustard oil was unaffected by previous capsaicin treatment. Thus, as in other species that have been examined (notably the rat), brief capsaicin treatment of rabbit skin nerves leads to a reduction in a neurogenic inflammatory response and in substance P content of the skin. However, unlike the rat, there is no degeneration of C-fibres. In the rabbit it is therefore possible to separate the neurotoxic, degenerative action of capsaicin from its ability to deplete substance P. The question of whether a similar dissociation between neurotoxic and other actions could be achieved in the rat by using lower capsaicin concentrations remains to be answered.
The main elements of neurogenic inflammation in the skin--antidromic vasodilatation, axon reflex flare and neurogenic plasma extravasation--are briefly described. New evidence is presented for a contribution from small myelinated fibres, as well as unmyelinated fibres, to antidromic vasodilatation. The mechanisms underlying flare are discussed and it is argued that weak coupling between C-fibre terminals must be important in determining the extent of spread of vasodilatation. The extent to which neurogenic factors contribute to a range of inflammatory models and to inflammatory disease states is discussed; it is argued that the importance of neurogenic mechanisms may have been underestimated.
First year pre-clinical medical students were taught about blood grouping and haemostasis using four audiotapes and associated booklets as the sole method of formal instruction. The audiotapes were readily accepted by the great majority of students as a replacement for lectures and those who listened to the tapes scored significantly higher in a multiple choice test 10 months later than did a previous years's student who had covered the same topics by means of lectures. If booklets are provided for each student, tapes are more expensive than lectures in terms of the time and running costs involved. By contrast, if booklets are sold or made available on loan with the audiotapes, then costs become equivalent when tapes are distributed to four to six average-sized medical schools and become increasingly cheaper as the number distributed increases. Other less readily quantifiable benefits of audiotape learning are discussed and it is concluded that in terms of both costs and effectiveness of learning, audiotapes can usefully replace a proportion of lectures in a conventional course. Consideration should be given to the provision of more space for audiotape tuition and less for formal lectures.
1. The firing frequency of polymodal nociceptor units with C-fibre axons was found to increase exponentially with skin temperature as the latter was raised linearly at 1 degree C/sec. Q10 values ranged from 3.6 to 120. 2. Following skin heating to 54--64 degrees C, average firing thresholds fell substantially. This sensitization was accompanied by a 46% increase in interval by interval variability of firing during heat stimulation. 3. Stopping the blood flow to the saphenous area by ligaturing the femoral or saphenous arteries had no significant effect on heat thresholds, on firing patterns during heat stimulation or on variability of firing in sensitized units. There were no changes in continuous, background firing during periods of arterial ligation. 4. It is concluded that if the maintenance of nociceptor heat sensitization depends on the continuous local production of chemical substances, these substances must either be rapidly broken down locally or able to move only slowly into blood vessels.
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The pain sensitivity of 49 healthy volunteers has been tested both before and during electro-acupuncture at two or three widely separated places on the body surface. Test areas fell into two categories. The "target" areas were within the part of the body that experienced acupuncturists predicted would be most affected by acupuncture of specified traditional points. "Non-target" control areas fell outside this zone of predicted maximal effect. The subjects and the observers who administered the tests knew that acupuncture anesthesia was being studied, but they did not know which areas were the "targets". Each subject was tested using at least two sensory testing methods. Altogether 4 different tests of pain sensitivity (pinprick discrimination, cold pain ratings, heat pain thresholds and pinch pain thresholds) were used. Small, but statistically highly significant, decreases in pain sensitivity occurred with all 4 tests during acupuncture. However, pain sensitivity fell by the same amount at "target" and "non-target" areas. The variability of the data was sufficiently low that moderate differences between areas would have been detected. The mechanism of "acupuncture anesthesia" is discussed in the light of these negative findings.
1. Seventy high threshold mechanoreceptor units (HTMs) with myelinated axons were isolated from the sural nerves of cats and rabbits. Thirteen cat and forty-two rabbit HTMs were testec by controlled, repeated heating of the skin of the foot or lower leg to noxious levels. 2. Many of the units (77% in the cat and 40% in the rabbit) fired to heating. Only six (11%) of these fired to the first brief heating to 50-55 degrees C. The rest required 2-6 heat trials before responding. 3. Heat responding units always became more sensitive with repeated heat stimulation but their mechanical sensitivity showed no comparable changes when heat sensitization occurred. 4. If these results are applicable to man, they suggest that HTMs play little role in generating the first pain that follows skin heating but that they may be involved in the increased sensitivity to heat pain (hyperalgesia) shown by skin previously injured by heating.
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