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Alfentanil, but not amitriptyline, reduces pain, hyperalgesia, and allodynia from intradermal injection of capsaicin in humans.

BACKGROUND: Intradermal injection of capsaicin produces brief pain followed by hyperalgesia and allodynia in humans, and the latter effects are mediated by spinal N-methyl-D-aspartate mechanisms. Amitriptyline recently was shown to antagonize N-methyl-D-aspartate receptors, and in this study, the authors sought to determine the effect of amitriptyline alone and with the opioid alfentanil on hyperalgesia and allodynia produced by intradermal injection of capsaicin. METHODS: Forty-six healthy volunteers in the general clinical research center received repeated intradermal injections of capsaicin (100 microg) alone or before and after systemic injection of 4 mg midazolam, 25 mg amitriptyline, alfentanil by computer-controlled infusion, or amitriptyline plus alfentanil. Acute pain and areas of mechanical hyperalgesia and allodynia were determined at specified intervals. Blood was obtained for alfentanil and amitriptyline assay. RESULTS: Capsaicin injection produced acute pain followed by hyperalgesia and allodynia. Alfentanil reduced these pain responses in a plasma-concentration-dependent manner, and reduction in hyperalgesia and allodynia correlated with reduction in acute pain. Amitriptyline alone had no effect and did not potentiate alfentanil. Alfentanil produced concentration-dependent nausea, an effect diminished by amitriptyline. DISCUSSION: These data correspond with previous studies in volunteers demonstrating reduction in hyperalgesia and allodynia after intradermal injection of capsaicin by systemically administered opioids, and they suggest that this reduction may be secondary to reduced nociceptive input by acute analgesia. These data do not support the use of acute systemic administration of amitriptyline for acute pain, hyperalgesia, and allodynia, although the roles of chronic treatment and spinal administration are being investigated.

Adult↗

Induction of partial resistance in calves to Cooperia spp. by repeated intradermal injections of adult worm extract.

The effect of repeated intradermal injections of small quantities of adult worm extract on the resistance of calves to Cooperia spp. was investigated. A group of five calves injected intradermally was less resistant than a similar group inoculated twice with infective larvae, but more resistant than a group of five calves kept as worm-free controls. The resistance was reflected by worm numbers, worm lengths, inhibition percentage of L4 larvae, number of eggs per female worm, egg production and by antibody titres.

Animals↗

Inhibitors of G-proteins and protein kinases reduce the sensitization to mechanical stimulation and the desensitization to heat of spinothalamic tract neurons induced by intradermal injection of capsaicin in the primate.

Intradermal injection of capsaicin results in sensitization of spinothalamic tract cells to brushing and pressure applied to the cutaneous receptive field in anesthetized monkeys. A significant increase in background activity also occurs immediately after capsaicin injection that lasts for at least 2 h. A 40-50% decrease in the response to noxious heat stimuli is also observed following capsaicin injection. This study investigated the spinal role of second messengers by extracellularly recording from spinothalamic tract cells and delivering inhibitors of second messenger pathways to the spinal cord by microdialysis. Blockade of protein kinases with the general protein kinase inhibitor, H7 (5.0 mM, n = 6), reduced the sensitization of the cells to brush and pressure. Blockade of protein kinase C with NPC15437 (10.0 mM, n = 10) reduced the increased background activity and the increased responses to brush. Blockade of protein kinase A with H89 (0.01 mM, n = 9) was most effective. H89 reduced the background activity, the increased responses to brush and press, and reversed the decreased response to noxious heat stimuli. Blockade of G-proteins with the general G-protein inhibitor, GDP-beta-S (1.0 mM, n = 9), reduced the background activity and the responses to brush and pressure without affecting the decreased response to heat. Thus, multiple intracellular messengers appear to be involved in the processing of central sensitization induced by activation of C-fibers following intradermal injection of capsaicin.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

Normal mouse skin lymphocyte, Langerhans cell, and keratinocyte responses to intradermal injections of interferon-alpha and interferon-gamma.

To investigate the skin immune responses induced by intradermal injections of interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma), normal C3H mice were injected intradermally with murine recombinant interferon-alpha (rIFN-alpha), interferon-gamma (rIFN-gamma), or the combination of rIFN-alpha and rIFN-gamma, three times per week for 2 or 4 weeks. Contralateral sites were similarly injected with placebo (saline). The results showed that after 6 or 12 injections of rIFN-alpha (10,000 IU/per injection), epidermal ATPase+ and Ia+ Langerhans cells (LGs) decreased significantly (p < 0.01 and p < 0.05) but dermal lymphocytic infiltrates, including CD3+ (pan-T cells), L3T4+ (T helper cells), Lyt-2+ (T suppressor/cytotoxic cells), MOMA+ (macrophages and monocytes), and dermal Ia+ cells, increased significantly (p < 0.01) compared with both saline injection sites and untreated skin. In contrast to rIFN-alpha, 6 injections of 10,000 IU rIFN-gamma failed to induce significant changes in either epidermal LGs or dermal lymphocytic infiltrates, except for an increase in dermal MOMA+ cells. High-dose rIFN-gamma injections (50,000 IU) strongly enhanced the expression of Ia antigen in epidermal keratinocytes (KCs), increased dermal lymphocytic infiltrates, and decreased the LGs in a similar pattern to that of rIFN-alpha. Furthermore, rIFN-gamma (50,000 IU) injections induced Ia antigen expression on the KCs in the contralateral saline injection areas, suggesting a systemic effect. Injections of a combination of rIFN-alpha and rIFN-gamma failed to show synergism for induction of skin immune responses.

Adenosine Triphosphatases↗

Intramuscular and intradermal injection of capsaicin: a comparison of local and referred pain.

The present study compared capsaicin-induced muscle and skin pain in humans. Twelve healthy subjects received, in a randomised, balanced order, 3 intramuscular (i.m.) injections into the brachioradial muscle: capsaicin 100 microg/1 ml, capsaicin 100 microg/20 microl or 1 ml solvent (Tween 80), and one intradermal injection (i.d.): capsaicin 100 microg/20 microl. Local and referred pain intensities and areas were assessed from 0 to 60 min after injection. Intradermal capsaicin produced more intense local pain than i.m. capsaicin in the first min (skin: 68+/-6, muscle: 51+/-6 mm VASxmin, P<0.05). In contrast, the local pain offset was later (muscle: 38+/-5, skin: 23+/-5 min, P<0.05) and referred pain was more frequent (muscle: 9/12, skin: 1/12 subjects, P<0.01) following i.m. capsaicin compared with i.d. capsaicin. Capsaicin (1 ml) produced significantly more pain than 20 microl i.m. (pain in the first min: 1 ml: 71+/-6, 20 microl: 51+/-6 VASxmin, P<0.05, offset: 1 ml: 50+/-4, 20 microl: 38+/-5 min, P<0.05). The different local and referred pain following identical noxious stimulation of muscle and skin indicates that the neurophysiological mechanisms underlying skin and muscle pain differs. The model with identical noxious stimulation of muscle and skin may be suitable for the study of differences in deep and superficial pain as seen in the clinic.

Adult↗

Enhanced inflammatory response with histiocytes and epithelioid cells in rabbits to the intradermal injection of supernatants of cultured cutaneous sarcoidal granulomas.

This study was designed to examine the inflammatory response in rabbits to intradermal injections of lymphokine-containing supernatants from cultured cutaneous sarcoidal granulomas (sarcoidal supernatant). Cell-free sarcoidal supernatants and concurrently incubated culture medium controls, alone or mixed with heat-inactivated K-S antigen or BLB, were injected intradermally into rabbits. These were, compared to control results, increased inflammatory reactions with histiocytes and epithelioid cells at the injection sites in 9 out of 11 experiments using sarcoidal supernatants mixed with K-S antigen and in 8 out of 10 experiments with these supernatants mixed with BLB. Sarcoidal supernatant alone, control medium, or normal saline solution produced no inflammatory response. Supernatants from cultured normal skin tissues obtained from sarcoid patients and those obtained from surgical patients free of sarcoidosis, when mixed with K-S antigen or BLB, showed variable inflammatory responses similar to the response seen with sarcoidal supernatants, but these were not significantly different from those of their own controls. It was concluded that lymphokines released locally may initiate and maintain the formation of sarcoidal granulomata.

Animals↗

Evaluation of the precision of intradermal injection of control substances for intradermal testing in clinically normal horses.

OBJECTIVE: To evaluate the precision of intradermal testing (IDT) in horses. ANIMALS: 12 healthy adult horses. PROCEDURE: IDT was performed on the neck of each horse by use of 2 positive control substances (histamine and phytohemagglutinin [PHA]) and a negative control substance. An equal volume (0.1 mL) for each injection was prepared to yield a total of 20 syringes ([4 concentrations of each positive control substance plus 1 negative control substance] times 2 positive control substances times 2 duplicative tests) for each side of the neck. Both sides of the neck were used for IDT; therefore, 40 syringes were prepared for each horse. Hair was clipped on both sides of the neck, and ID injections were performed. Diameter of the skin wheals was recorded 0.5, 4, and 24 hours after ID injection. RESULTS: Intra- and interhorse skin reactions to ID injection of histamine and PHA resulted in wheals of uniform size at 0.5 and 4 hours, respectively. Significant intra- and interhorse variation was detected in wheals caused by PHA at 24 hours. CONCLUSIONS AND CLINICAL RELEVANCE: ID injection of histamine and PHA caused repeatable and precise results at 0.5 and 4 hours, respectively. Concentrations of 0.005 mg of histamine/mL and 0.1 mg of PHA/mL are recommended for use as positive control substances for IDT in horses. This information suggests that consistent wheal size is evident for ID injection of control substances, and variation in wheals in response to ID injection of test antigens results from a horse's immune response to specific antigens.

Allergens↗