Morphine Analgesia Modification in Normotensive and Hypertensive Female Rats after Repeated Fluoxetine Administration

Abstract

The purpose of this investigation was to determine through the use of fluoxetine the effect of administering a serotonin reuptake inhibitor over several days on the antinociceptive action of l-morphine type opioid receptor agonist. Investigations were performed on rats of both sexes, both the WKY normotensive strains as well as on the SHR genetically conditioned hypertensive strains. Results showed that the efficacy of morphine analgesia is higher in the SHR strain compared to normotensive rats (WKY). Surprisingly, repeated administration of fluoxetine reduced morphine analgesia, with the weakening of opioid antinociceptive action comparable to the duration of serotonin reuptake inhibitor administration. It was also concluded that the antinociceptive action of morphine in female rats and the alteration of its efficacy as a result of fluoxetine premedication for several days depend on oestrus cycle phase. The highest sensitivity of female rats to morphine was reported in the dioestrus and oestrus phases; much lower values were reported for the metoestrus phase.For decades, young male rats have been the basic group of animals used in research addressing the pharmacological consequences of administering drugs, with research results being extrapolated to the entire population. It is now well-known that males and females may react differently to the administration of drugs. Significant differences have been reported for lmorphine type opioid receptor agonist, which exhibits distinct sexual dimorphism. Sex-dependent differentiation has been reported for sensitivity to analgesic action of such a l-type opioid receptor agonist [1][2][3][4], quickness in developing tolerance and dependence [5], as well as release substance P [6]. Also, a number of investigations have confirmed the influence of morphine on the functioning of the female sexual system. It has been reported that chronic administration of morphine disrupts the oestrus cycle [5]. The effect of sex hormones on the development of sex-dependent differentiation is also shown by the fact that many sex dimorphic features only develop postpuberty. Neither sex-dependent differentiation in heart rate [7] nor pain sensitivity in the case of many pain conditions [8,9] has been reported pre-puberty. It has also been shown that sex steroids modulate large-artery stiffness, thus -in addition to genetic factors -affecting frequency of isolated systolic hyperpressure occurrence [7].Patients treated with morphine often also require use of antidepressants, which include selective serotonin reuptake inhibitors (SSRI). No complete mechanism of SSRI antinociceptive action has yet been offered. Due to the more effective performance analgesic action of fluoxetine compared to the placebo in patients with depression, it is possible that its analgesic efficacy could be related to antidepressant activity [10]. Its place of action could be the same as for the l-type opioid receptor agonists [11], but antinociceptive action could also involve the cholinergic, noradrenergic and G...

The Wistar Kyoto Rat: A Model of Depression Traits

“…WKYs also exhibit exacerbated nociceptive responses to visceral pain [ 43 ] and prolonged inflammatory stimuli [ 42 , 44 ]. Altered pain sensitivity in WKYs compared to other strains is further supported by their hypoanalgesic responsiveness to equivalent circulating plasma levels of morphine [ 45 - 47 ]. These findings are consistent with depression in humans, which is accompanied by pain-related symptoms at an estimated prevalence of 65% [ 48 ].…”

The role of gonadal hormones in regulating opioid antinociception

“…Kosiorek et al. reported that the sensitivity of female rats to subcutaneous administration of morphine in the diestrus and oestrous phases was higher than that in the metestrus phase [ 30 ]. The antinociceptive efficacy of morphine microinjected into the ventrolateral periaqueductal grey (PAG) was found to be highest in female diestrus phase of rats [ 31 ].…”

The pathophysiological role of serotonin receptor systems in opioid analgesia and tolerance

“…112 It has been reported that blockade of 5-HT 7 receptors inhibit the opioid analgesia. 113 In addition, evidences indicate that the activation 5-HT 7 receptors decrease morphine withdrawal.…”