PubMed · 2921908
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K G Henriksson, A Bengtsson. 1989-02-22. [Fibromyalgia--an entity?].. https://pubmed.ncbi.nlm.nih.gov/2921908/
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Interstitial cells of Cajal (ICC) provide pacemaker activity in some smooth muscles. The nature of the pacemaker conductance is unclear, but studies suggest that pacemaker activity is due to a voltage-independent, Ca(2+)-regulated, non-selective cation conductance. We investigated Ca(2+)-regulated conductances in murine intestinal ICC and found that reducing cytoplasmic Ca(2+) activates whole-cell inward currents and single-channel currents. Both the whole-cell currents and single-channel currents reversed at 0 mV when the equilibrium potentials of all ions present were far from 0 mV. Recordings from on-cell patches revealed oscillations in unitary currents at the frequency of pacemaker currents in ICC. Voltage-clamping cells to -60 mV did not change the oscillatory activity of channels in on-cell patches. Depolarizing cells with high external K(+) caused loss of resolvable single-channel currents, but the oscillatory single-channel currents were restored when the patches were stepped to negative potentials. Unitary currents were also resolved in excised patches. The single-channel conductance was 13 pS, and currents reversed at 0 mV. The channels responsible were strongly activated by 10(-7) M Ca(2+), and 10(-6) M Ca(2+) reduced activity. The 13 pS channels were strongly activated by the calmodulin inhibitors calmidazolium and W-7 in on-cell and excised patches. Calmidazolium and W-7 also activated a persistent inward current under whole-cell conditions. Murine ICC express Ca(2+)-inhibited, non-selective cation channels that are periodically activated at the same frequency as pacemaker currents. This conductance may contribute to the pacemaker current and generation of electrical slow waves in GI muscles.
Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of the structure-activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compounds for mu-, delta-, and kappa-receptors were determined in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivatives of mitragynine, i.e., mitragynine pseudoindoxyl (2) and 7-hydroxymitragynine (12), were found as opioid agonists with higher potency than morphine in the experiment with guinea pig ileum. In addition, 2 induced an analgesic activity in the tail flick test in mice.
Intrathecal administration of 5-HT(2) receptor agonists produces an anti-allodynic effect in a rat model of neuropathic pain. Several non-serotonergic neurotransmitters have been implicated these anti-nociceptive effects. In the present study, intrathecal pre-treatment with the muscarinic receptor antagonist atropine (10 and 30 microg) and pirenzepine (10 microg) reversed the anti-allodynic effect of the 5-HT(2) receptor agonist alpha-methyl-5-hydroxytryptamine, unlike various other antagonists. Thus, muscarinic receptors may be involved in the anti-allodynic action of intrathecally injected 5-HT(2) receptor agonist.