Pharmacological research : the official journal of the Italian Pharmacological Society
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Intracellular acidosis is one of the alterations occurring in cardiac ischemia and has been discussed to be important in altering excitation--contraction coupling. The aim of this study was to determine how intracellular acidosis may affect intracellular sodium and calcium handling. Cardiomyocytes were isolated from the hearts of adult male guinea-pigs by standard techniques and superfused with modified Tyrode's solution at room temperature, either HEPES buffered containing 10 mM NaHCO(3)or HEPES buffered without NaHCO(3), in order to examine a possible interaction with the sodium bicarbonate symport. ⋯ We conclude that under these experimental conditions intracellular acidification causes an increase in [Na(+)](i)without changing intracellular Ca(2+)or the L-type calcium current. In addition in bicarbonate-buffered systems the acidosis-induced increase in sodium is enhanced which may involve the Na(+)/HCO(3)(minus sign)symport. The effect of cariporide (Hoe 642) in intracellular acidosis seems to be based on antagonization of the rise in intracellular sodium rather than calcium in this model.
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The activity of nefopam, a centrally acting compound, not structurally related to other analgesics, was examined in acute and postoperative thermal pain models in the rat. Its antinociceptive potency was evaluated using heat noxious stimuli either in intact or in injured animals after skin and muscular incisions. In the hot plate and in the plantar tests, nefopam after acute administration by different routes exhibited a dose-dependent attenuation of the nociceptive responses at 10-30 mg x kg(-1) by intraperitoneal or subcutaneous administration, at 60 mg x kg(-1) by oral dosing, and from 3 mg x kg(-1) after intravenous injection. ⋯ In the same conditions, morphine and tramadol displayed antinociceptive activities. As the plantar test provides a good index of nociception in humans, these results point out the usefulness of nefopam for attenuating moderate to severe pain, and for postoperative analgesia. In conclusion, nefopam has shown potent properties to reduce thermal hypersensitivity after acute or postoperative pain in rats.
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Rheumatic diseases are the most prevalent causes of disability in western countries, and non-steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly used remedies. However, NSAIDs cause several serious adverse effects, the most important being from gastric injury to gastric ulceration and renal damage. Attempts to develop non-steroidal anti-inflammatory remedies devoid of these shortcomings-especially gastrointestinal toxicity-have followed several strategies. ⋯ Such compounds retain the activity of classical NSAIDs, while avoiding their main drawbacks, in that curtailed production of gastroprotective prostaglandins is associated with a concurrent curtailed production of the gastro-damaging and bronchoconstrictive leukotrienes. Moreover, thanks to their mechanism of action, dual acting anti-inflammatory drugs could not merely alleviate symptoms of rheumatic diseases, but might also satisfy, at least in part, the criteria of a more definitive treatment. Indeed, leukotrienes are pro-inflammatory, increase microvascular permeability, are potent chemotactic agents and attract eosinophils, neutrophils and monocytes into the synovium.
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We investigated the effect of topical application of capsaicin cream on withdrawal latency in the hind foot of rat in response to radiant heat in an experimental model of neuropathic pain. A neuropathic state was induced by loose ligation of the sciatic nerve with chromic gut suture. A marked thermal hyperalgesia was observed in response to heat stimulus applied to the operated side from 3 days through 2 weeks, followed by a gradual return to the control level by 35 days after surgery. ⋯ Pretreatment with MK-801 (0.5 mg kg(-1), i.p.), but not with CNQX (0.5 mg kg(-1), i.p.), reversed the thermal hyperalgesia following nerve injury. Neither of RP67580 (1--10 mg kg(-1), i.p.) nor SR48968 (1--10 mg kg(-1), i.p.) had any effect on the withdrawal latency in the injured and non-injured hind paw. These results suggest that although the manifestation of effectiveness may be delayed by changes in networks of neurotransmitters related to the nociceptive pathways following nerve injury, longer-term repetitive application of capsaicin cream has a significant therapeutic effect on subjects with painful peripheral neuropathy.
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Comparative Study
The influence of divalent cations on the analgesic effect of opioid and non-opioid drugs.
It is generally accepted that divalent cations are involved in the nociceptive pathway. The effect of systemic co-administration of magnesium sulfate and calcium channel blockers (nifedipine, verapamil) on the analgesic effect of opioid (mixed mu/kappa: butorphanol) and non-opioid drugs (paracetamol) was investigated. Albino mice and rats were used as experimental animals. ⋯ We conclude that the systemic co-administration of calcium channel blockers potentiated the analgesic effect of butorphanol against thermal, mechanical and chemical pain but enhanced that of paracetamol only against mechanical and chemical pain. Magensium sulfate enhanced the analgesic effect of butorphanol, but not that of paracetamol. These findings, merit further studies in animals and humans to evaluate the potential therapeutic benefits of such interactions.