Centhaquin attenuates hyperalgesia and non-evoked guarding in a rat model of postoperative pain primarily through α2B-adrenoceptors.

Centhaquin has been shown to produce antinociception in the mouse hot plate and tail flick assays through the opioid, the α2A and α2B adrenoceptors. Present study was conducted to determine the effects of centhaquin in a rat model of postoperative pain. Involvement of opioid, and adrenergic receptors was assessed by pretreating rats with antagonists at the opioid (naloxone), α2-(atipamezole) or α2B-(imiloxan) adrenergic receptors. Postoperative pain was induced by hind paw plantar incision in male Sprague Dawley rats. Antihyperalgesic effects were determined by measurement of paw withdrawal latencies and withdrawal force, using dynamic von Frey filaments; attenuation of non-evoked guarding was measured by assigning pain scores to spontaneous behaviors. Rotarod test was used to determine motor impairment. Animals received saline, centhaquin or antagonist plus centhaquin. Centhaquin produced dose-dependent antihyperalgesic effect and attenuation of non-evoked guarding behavior, versus saline treated rats (P<0.05). Naloxone partially blocked while atipamezole and imiloxan significantly reversed centhaquin's antihyperalgesic effects (P<0.05). Attenuation of non-evoked guarding behavior was also blocked, but was not statistically significant. Imiloxan produced a greater block compared to atipamezole while naloxone had no significant effect. Rotarod testing indicated that centhaquin did not cause motor impairment. This is the first report demonstrating centhaquin antinociception in the rat postoperative pain model. Opioid, α2 adrenergic, and particularly α2B adrenergic receptors are involved in mediating antihyperalgesia while attenuation of nonevoked guarding is mediated by α2B/α2 adrenergic receptors. Centhaquin could be an effective non-sedating alternative in treating postoperative pain in ambulatory surgeries.

Leonard MG ，Jung S ，Andurkar SV ，Gulati A ... -  《-》

Centhaquin antinociception in mice is mediated by α2A- and α2B- but not α2C-adrenoceptors.

The use of clonidine as a primary and adjuvant analgesic is well-documented. It is known that imidazoline and α2-adrenoceptors are involved in clonidine antinociception. Clonidine also produces antihypertensive actions mediated through the central nervous system. We have reported that centhaquin, a centrally-acting anti-hypertensive drug produces its hypotensive effect through a mechanism of action similar to clonidine. Centhaquin has also been shown to possess significant antinociceptive activity. Centhaquin antinociception is partially blocked by yohimbine, idazoxan, and naloxone; however, the involvement of specific adrenoceptor subtypes (α2A, α2B, or α2C) in centhaquin antinociception is unknown. The present study was conducted to determine antinociceptive properties of centhaquin citrate, a water soluble salt of centhaquin, and involvement of α2A-, α2B-, or α2C-adrenoceptors in centhaquin citrate antinociception in mice. BRL-44408 (α2A-adrenoceptor antagonist), imiloxan (α2B-adrenoceptor antagonist) and JP-1302 (α2C-adrenoceptor antagonist) were used to determine the involvement of α2A-, α2B-, or α2C-adrenoceptors, respectively. Antinociceptive (tail-flick and hot-plate) latencies were determined in male Swiss-Webster mice treated with centhaquin citrate alone and in combination with BRL-44408, imiloxan, or JP-1302. Centhaquin citrate produced significant antinociception in mice (P<0.05) which was unaffected by JP-1302 (P>0.05) but blocked by BRL-44408 (tail-flick test: 49.75% decrease, P<0.05; hot-plate test: 49.12% decrease, P<0.05) and imiloxan (tail-flick test: 46.98% decrease, P<0.05; hot-plate test: 46.42% decrease, P<0.05). This is the first report demonstrating centhaquin citrate antinociception and its blockade by BRL-44408 and imiloxan. We conclude that α2A and α2B but not α2C adrenoceptors are involved in centhaquin antinociception in mice.

Bhalla S ，Ali I ，Andurkar SV ，Gulati A ... -  《-》

Assessment of the analgesic effect of centhaquin in mouse tail flick and hot-plate tests.

Centhaquin is a centrally acting hypotensive drug like clonidine. Clonidine also produces analgesia and hypothermia in mice and potentiates morphine analgesia. Clonidine analgesia is blocked by idazoxan and naloxone while it is potentiated by BQ123 and sulfisoxazole. This study was conducted to determine the analgesic and hypothermic properties of centhaquin, and to assess whether it potentiates morphine analgesia. Yohimbine (α(2)-adrenergic antagonist), idazoxan (imidazoline/α(2)-adrenergic antagonist), naloxone (opioid antagonist), and BQ123 and sulfisoxazole (endothelin ET(A) antagonists) were used to study the involvement of these receptors in centhaquin analgesia and hypothermia. Analgesic (tail flick and hot-plate tests) latencies and body temperatures were measured in male Swiss Webster mice treated with vehicle plus centhaquin, antagonists plus centhaquin or centhaquin plus morphine. Centhaquin produced dose-dependent analgesia which was partially blocked by yohimbine, idazoxan and naloxone. BQ123 and sulfisoxazole did not affect centhaquin analgesia. Morphine analgesia was not potentiated by centhaquin. Centhaquin produced mild hypothermia which was not blocked by yohimbine, idazoxan, naloxone, BQ123 or sulfisoxazole. This is the first report demonstrating the analgesic activity of centhaquin. The α(2)-adrenergic, imidazoline and opioid receptors are involved in mediating centhaquin analgesia. Endothelin ET(A) receptors do not play a role in centhaquin analgesia; centhaquin does not augment morphine analgesia.

Andurkar SV ，Gulati A 《-》

Antihypersensitivity effects of tramadol hydrochloride in a rat model of postoperative pain.

Kimura M ，Obata H ，Saito S 《-》

The mechanisms of antihyperalgesic effect of topiramate in a rat model of inflammatory hyperalgesia.

Recent studies have shown that topiramate, a structurally novel anticonvulsant, exerts antinociceptive activity in animal models of neuropathic, acute somatic, and visceral pain. This study was aimed to examine: (i) the effects of systemically and locally peripherally administered topiramate in the rat inflammatory pain model and (ii) the potential role and site(s) of gamma-aminobutyric acid (GABA), opioid, and adrenergic receptors in topiramate's antihyperalgesia. Rats received intraplantar (i.pl.) injections of the pro-inflammatory compound carrageenan. A paw pressure test was used to determine: (i) the effect of systemic and local peripheral topiramate on carrageenan-induced hyperalgesia and (ii) the effects of systemic and local peripheral bicuculline (selective GABAA receptor antagonist), naloxone (nonselective opioid receptor antagonist), and yohimbine (selective α2-adrenergic receptor antagonist) on topiramate-induced antihyperalgesia. Systemic topiramate (40-160 mg/kg; p.o.) produced a significant dose-dependent reduction in the paw inflammatory hyperalgesia induced by carrageenan. The antihyperalgesic effect of systemic topiramate was significantly decreased by systemic bicuculline (0.5-1 mg/kg; i.p.), naloxone (2-5 mg/kg; i.p.), and yohimbine (1-3 mg/kg; i.p.). Local peripheral topiramate (0.03-0.34 mg/paw; i.pl.) also produced significant dose-dependent antihyperalgesia, which was significantly depressed by local peripheral yohimbine (0.05-0.2 mg/paw; i.pl.) but not by local peripheral bicuculline (0.15 mg/paw; i.pl.) or naloxone (0.1 mg/paw; i.pl.). The results suggest that topiramate produces systemic and local peripheral antihyperalgesia in an inflammatory pain model, which is, at least partially, mediated by central GABAA and opioid receptors and by peripheral and most probably central α2-adrenergic receptors. These findings contribute to better understanding of topiramate's action in pain states involving inflammation.

Paranos SLj ，Tomić MA ，Micov AM ，Stepanović-Petrović RM ... -  《-》