Preliminary clinical studies of testosterone therapy in male patients with coronary artery disease raised promising results. However, there is no study on in vitro effects of testosterone in human isolated arteries. We investigated the effect of testosterone on contractile tone of human isolated internal mammary artery. The responses in human internal mammary artery (IMA) were recorded isometrically by a force-displacement transducer in isolated organ baths. Testosterone (10 nM to 100 microM) was added cumulatively to organ baths either at rest or after precontraction with KCl (68 mM) and PGF2alpha (10 microM). Testosterone-induced relaxations were tested in the presence of cyclooxygenase inhibitor indomethacin (10 microM), nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 1 microM), nonselective large-conductance Ca2+-activated and voltage-sensitive K+ channel inhibitor tetraethylammonium (TEA, 1 mM), ATP-sensitive K+ channel inhibitor glibenclamide (GLI, 100 microM), and voltage-sensitive K+ channel inhibitor 4-aminopyridine (4-AP, 1 mM). Testosterone produced relaxation in human IMA (Emax 33% and 41% of KCl- and PGF2alpha-induced contraction, respectively). Vehicle had no significant relaxant effect. Except for TEA, the relaxation at low concentrations is not affected by either K+ channel inhibitors (GLI and 4-AP) or L-NAME and indomethacin. We report for the first time that supraphysiological concentrations of testosterone induce relaxation in IMA. This response may occur in part via large-conductance Ca2+-activated K+ channel-opening action.
Opioids and cannabinoids produce antinociception through both spinal and supraspinal action. Both opioids and cannabinoids also have important peripheral action. Many previous studies indicate that systemically administered cannabinoids enhance antinociceptive properties of opioids. Experiments were conducted to test the hypothesis that topical cannabinoids would enhance the topical antinociceptive effects of morphine. Antinociception was measured in the radiant tail-flick test after immersion of the tail of mice into a solution of dimethyl sulfoxide (DMSO) containing WIN 55, 212-2, a cannabinoid agonist and morphine, an opioid agonist. Morphine and WIN 55, 212-2 produce time dependent topical analgesic effects limited to the portion of the tail exposed to drugs. WIN 55, 212-2 had a potency lower than that of morphine. The topical antinociceptive effects of WIN 55, 212-2 were blocked by systemic pretreatment of cannabinoid CB1 receptor selective antagonist, AM 251. This suggests that topical antinociceptive effects of WIN 55, 212-2 involve CB1 receptors. Combination of topical WIN 55, 212-2 with topical morphine yielded significantly greater analgesic effects than that of topical morphine alone. The ability of the CB1 receptor antagonist AM 251 to antagonize the enhancement of antinociception of morphine by WIN 55, 212-2 indicates that WIN 55, 212-2 acts through a CB1 receptor to enhance the potency of topical morphine. Additionally, spinally administered ineffective doses of WIN 55, 212-2 potentiated the antinociceptive effects of topical morphine. These results demonstrate an antinociceptive interaction between topical opioids with topical, and spinal cannabinoids. These observations are significant in using of topical combination of cannabinoid and morphine in the management of pain.
Analgesic effects of cannabimimetic compounds have been known to be related to their central effects. Cannabinoid receptors also exist in the periphery but their role in pain perception has been remained to be clarified. Therefore, we assessed topical antinociceptive effects of WIN 55, 212-2, a mixed CB(1) and CB(2) receptors agonist, in mice using tail-flick test. Immersion of the tail of mouse into the WIN 55, 212-2 solution produced dose-dependent antinociception. This antinociceptive activity was limited to the portion of the tail exposed to WIN 55, 212-2. The antinociceptive response was dependent on duration of exposure to WIN 55, 212-2 solution. The topical antinociceptive effects of WIN 55, 212-2 were dose dependently blocked by topical pretreatment of CB(1) receptor-selective antagonist, AM 251. Thus, topical antinociceptive action of WIN 55, 212-2 involve CB(1) receptors. Intrathecal (i.th.) administration of WIN 55, 212-2 produced a dose-dependent antinociceptive effect. Interestingly, ineffective i.th. doses of WIN 55, 212-2 produced a marked antinociception when combined with topical application of WIN 55, 212-2 and topical antinociceptive effect was potentiated. The dose-response curve of i.th. WIN 55, 212-2 was shifted to the left 15-fold by topical WIN 55, 212-2. This finding suggests that there is an antinociceptive synergy between peripheral and spinal sites of cannabinoid action and it also implicates that local activation of cannabinoid system may regulate pain initiation in cutaneous tissue. Our findings support that cannabinoid system participates in buffering the emerging pain signals at the peripheral sites in addition to their spinal and supraspinal sites of action. In addition, an antinociceptive synergy between topical and spinal cannabinoid actions exists. These results also indicate that topically administered cannabinoid agonists may reduce pain without the dysphoric side effects and abuse potential of centrally acting cannabimimetic drugs.
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