Study of adrenergic, imidazoline, and endothelin receptors in clonidine-, morphine-, and oxycodone-induced changes in rat body temperature.

The potentiation of morphine or oxycodone analgesia by endothelin-A (ET(A)) receptor antagonists and imidazoline/α(2)-adrenergic agonists is well documented. However, the effect of morphine or oxycodone in combination with an ET(A) receptor antagonist or an imidazoline/α(2) adrenergic agonist on body temperature is not known. The present study was carried out to study the role of ET(A) and imidazoline/α(2) adrenergic receptors in body temperature effects of morphine, oxycodone, and clonidine in rats. Body temperature was determined in male Sprague-Dawley rats treated with morphine, oxycodone, or clonidine. Yohimbine, idazoxan, and BMS182874 were used to determine the involvement of α(2)-adrenergic, imidazoline, and ET(A) receptors, respectively. Morphine and oxycodone produced hyperthermia which was not affected by α(2)-adrenergic antagonist yohimbine, imidazoline/α(2)-adrenergic antagonist idazoxan, or ET(A) receptor antagonist BMS182874. Clonidine alone produced hypothermia that was comparable to the hypothermia observed with clonidine plus morphine or oxycodone. The hypothermic effect of clonidine was blocked by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared to yohimbine. Clonidine hypothermia was not affected by BMS182874. This is the first report demonstrating that ET(A) receptors do not influence morphine- and oxycodone- induced hyperthermia or clonidine-induced hypothermia. Imidazoline receptors and α(2)-adrenergic receptors are involved in clonidine-induced hypothermia, but not in morphine- and oxycodone-induced hyperthermia.

Bhalla S ，Andurkar SV ，Gulati A 《-》

Determination of adrenergic and imidazoline receptor involvement in augmentation of morphine and oxycodone analgesia by clonidine and BMS182874.

Gulati A ，Bhalla S ，Matwyshyn G ，Zhang Z ，Andurkar SV ... -  《-》

Tramadol antinociception is potentiated by clonidine through α₂-adrenergic and I₂-imidazoline but not by endothelin ET(A) receptors in mice.

Tramadol is a centrally acting analgesic that acts via μ-opioid agonism and by blocking the neuronal uptake of norepinephrine and serotonin. Clonidine potentiates the antinociceptive effects of tramadol; however the receptors involved in this potentiation have not been studied. Endothelin ET(A) receptor antagonists potentiate antinociceptive effects of morphine and oxycodone; however the effects of endothelin ET(A) receptor antagonists on tramadol antinociception have not been evaluated. This study was conducted to determine the effect of clonidine on tramadol antinociception; the role of opioid, α₂-adrenergic and I₂-imidazoline receptors in clonidine potentiation of tramadol antinociception; and the effect of endothelin ET(A) receptor antagonists in modulating tramadol antinociception. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with tramadol; clonidine plus tramadol; or antagonists plus tramadol. Mice were pretreated with naloxone (opioid antagonist), yohimbine (α₂-adrenoceptor antagonist), idazoxan (α₂-adrenoceptor/I₂-imidazoline antagonist), BMS182874 or BQ123 (endothelin ET(A) receptor antagonists) to study the involvement of these receptors. Tramadol produced a dose dependent increase in antinociceptive latencies. Tramadol antinociception was partially blocked by naloxone but not by yohimbine or idazoxan. Clonidine potentiated tramadol antinociception; potentiation was blocked by naloxone, yohimbine and idazoxan. Idazoxan produced a more pronounced blockade of potentiation than yohimbine. BMS182874 or BQ123 had no effect on tramadol antinociception, indicating that endothelin ET(A) receptors are not involved in tramadol antinociception in mice. Results demonstrate the involvement of opioid but not α₂-adrenergic/I₂-imidazoline receptors in tramadol antinociception and that opioid, α₂-adrenergic and I₂-imidazoline receptors are involved in clonidine potentiation of tramadol antinociception.

Andurkar SV ，Gendler L ，Gulati A 《-》

Involvement of α₂-adrenoceptors, imidazoline, and endothelin-A receptors in the effect of agmatine on morphine and oxycodone-induced hypothermia in mice.

Potentiation of opioid analgesia by endothelin-A (ET(A)) receptor antagonist, BMS182874, and imidazoline receptor/α₂-adrenoceptor agonists such as clonidine and agmatine are well known. It is also known that agmatine blocks morphine hyperthermia in rats. However, the effect of agmatine on morphine or oxycodone hypothermia in mice is unknown. The present study was carried out to study the role of α₂-adrenoceptors, imidazoline, and ET(A) receptors in morphine and oxycodone hypothermia in mice. Body temperature was determined over 6 h in male Swiss Webster mice treated with morphine, oxycodone, agmatine, and combination of agmatine with morphine or oxycodone. Yohimbine, idazoxan, and BMS182874 were used to determine involvement of α₂-adrenoceptors, imidazoline, and ET(A) receptors, respectively. Morphine and oxycodone produced significant hypothermia that was not affected by α₂-adrenoceptor antagonist yohimbine, imidazoline receptor/α₂ adrenoceptor antagonist idazoxan, or ET(A) receptor antagonist, BMS182874. Agmatine did not produce hypothermia; however, it blocked oxycodone but not morphine-induced hypothermia. Agmatine-induced blockade of oxycodone hypothermia was inhibited by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared with yohimbine. Combined administration of BMS182874 and agmatine did not produce changes in body temperature in mice. However, when BMS182874 was administered along with agmatine and oxycodone, it blocked agmatine-induced reversal of oxycodone hypothermia. This is the first report demonstrating that agmatine does not affect morphine hypothermia in mice, but reverses oxycodone hypothermia. Imidazoline receptors and α₂-adrenoceptors are involved in agmatine-induced reversal of oxycodone hypothermia. Our findings also suggest that ET(A) receptors may be involved in blockade of oxycodone hypothermia by agmatine.

Bhalla S ，Andurkar SV ，Gulati A 《-》

Determination of α(2)-adrenoceptor and imidazoline receptor involvement in augmentation of morphine and oxycodone analgesia by agmatine and BMS182874.

Studies have demonstrated that clonidine (α(2)-adrenoceptor and imidazoline receptor agonist) and BMS182874 (endothelin ET(A) receptor antagonist) potentiate morphine and oxycodone analgesia. Agmatine, an endogenous clonidine-like substance, enhances morphine analgesia. However, its effect on oxycodone analgesia and its interaction with endothelin ET(A) receptor antagonists are not known. The present study was performed to determine the effect of agmatine on morphine and oxycodone analgesia and the involvement of α(2)-adrenoceptors, imidazoline receptors, opioid receptors, and endothelin receptors. Antinociception at various time intervals was determined by the tail-flick latency method in mice. Agmatine produced dose-dependent increase in tail-flick latency, while BMS182874 did not produce any change over the 360-min observation period. Agmatine significantly potentiated morphine as well as oxycodone analgesia which was not altered by BMS182874. BMS182874 pretreatment did not increase the analgesic effect produced by agmatine alone. Agmatine-induced potentiation of morphine and oxycodone analgesia was blocked by idazoxan (imidazoline receptor/α(2)-adrenoceptor antagonist) and yohimbine (α(2)-adrenoceptor antagonist). BMS182874-induced potentiation of morphine or oxycodone analgesia was not affected by yohimbine. However, idazoxan blocked BMS182874-induced potentiation of oxycodone but not morphine analgesia. This is the first report demonstrating that agmatine potentiates not only morphine but also oxycodone analgesia in mice. Potentiation of morphine and oxycodone analgesia by agmatine appears to involve α(2)-adrenoceptors, imidazoline receptors, and opioid receptors. In addition, imidazoline receptors may be involved in BMS182874-induced potentiation of oxycodone but not morphine analgesia. It is concluded that agmatine may be used as an adjuvant in opiate analgesia.

Bhalla S ，Rapolaviciute V ，Gulati A 《-》