Comparison of the Antinociceptive Response to Morphine and Morphine-Like Compounds in Male and Female Sprague-Dawley Rats

Abstract

Male rats are more sensitive to the antinociceptive effects of morphine than female rats. This difference is seen across several rat strains using a variety of nociceptive stimuli. However, the literature in regard to sex differences in antinociceptive responses to -opioids other than morphine is less consistent. The present study was designed to examine whether there is a structure-activity rationale that determines which -opioids will show a differential antinociceptive response between male and female rats. A series of morphinans closely related in structure to morphine, namely, codeine, heroin, hydrocodone, hydromorphone, oxymorphone, and oxycodone, were examined for their antinociceptive activity in male and female Sprague-Dawley rats and compared with the structurally unrelated -opioid agonists methadone and fentanyl. Antinociception was measured by the warm-water tail-withdrawal assay. The results show that morphine is more potent in males compared with females Ͼ hydromorphone ϭ hydrocodone ϭ oxymorphone, but there was no observable sex difference in the antinociceptive potency of codeine, heroin, oxycodone, methadone, or fentanyl. The potency to stimulate guanosine 5Ј-O-(3-[ 35 S]thio)triphosphate ([ 35 S]GTP␥S) binding and binding affinity of the various morphinans was compared in rat glioma C6 cells expressing the rat -opioid receptor; relative efficacy was also compared by stimulation of [35 S]GTP␥S binding in slices of rat brain thalamus. The presence of a sex difference in antinociceptive responsiveness was not related to drug potency, efficacy, or affinity. Consequently, it is likely that differential metabolism of the opioid, possibly by glucuronidation, determines the presence or absence of a sex difference.Male rats are more sensitive to the antinociceptive effects of morphine than female rats. These results seem to be consistent over several types of antinociceptive assays using a variety of nociceptive stimuli and behavioral endpoints.

Activation of Opioid Receptor Like-1 Receptor in the Spinal Cord Produces Sex-Specific Antinociception in the Rat: Estrogen Attenuates Antinociception in the Female, whereas Testosterone Is Required for the Expression of Antinociception in the Male

“…Women exhibit enhanced sensitivity to experimental pain (for review, see Fillingim and Maixner, 1995) and experience a greater prevalence of pain disorders (Fillingim and Maixner, 1995) (for review, see Berkley, 1997). Sex-related differences in pain modulation by activation of G-proteincoupled receptors such as opioid ( and ) and ␣ 2 noradrenergic receptors have been demonstrated in human and animal studies (Gear et al, 1996;Mitrovic et al, 2003;Mogil et al, 2003;Fillingim and Gear, 2004;Nag and Mokha, 2006;Peckham and Traynor, 2006).…”

Comparative Pharmacological Profiles of Morphine and Oxycodone under a Neuropathic Pain-Like State in Mice: Evidence for Less Sensitivity to Morphine

“…However, recent studies have shown that these MOR agonists and metabolites have interesting pharmacological differences (Peckham and Tratnor, 2006;Lemberg et al, 2006a, b). Oxycodone has been in clinical use since 1917.…”

Neuropsychiatric pharmaceuticals and illicit drugs in wastewater treatment plants: a review

“…log P [149,150] (octanol-water) A. G. Asimakopoulos and K. Kannan compounds in untreated wastewater and during wastewater treatment. [10] Glucuronidated morphine has been detected in wastewater influent at low concentrations (2-18 ng L À1 ), demonstrating the cleavage of the glucuronide bond in wastewater treatment processes.…”

“…Methadone is also prescribed for patients in substance-abuse programs and has a readily quantifiable metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) ( Table 1). [23,28,30,31] Morphine is excreted in urine as morphine-3b-D-glucuronide and morphine6b-D-glucuronide or as free morphine. [10] Codeine is excreted in urine mainly (,70 %) as codeine-6-glucuronide.…”