estradiol-3-benzoate and Pain

Primary dysmenorrhea affects the quality of life in young women, particularly school and work performance. This study investigated the mechanisms of penehyclidine hydrochloride (PHC) efficacy on a rat model of primary dysmenorrhea. The model was induced by injecting both estradiol benzoate and oxytocin. Different doses of PHC were administrated intraperitoneally following estradiol benzoate administration. Writhing scores were assessed, and pathological changes of the uterus were observed via hematoxylin and eosin staining. Western blot and real-time PCR were used to evaluate the expression level of the M

Topics: Animals; Behavior, Animal; Calcium; Disease Models, Animal; Dysmenorrhea; Estradiol; Female; Oxytocin; Pain; Quinuclidines; Rats, Sprague-Dawley; Receptor, Muscarinic M3; Toll-Like Receptor 3; Toll-Like Receptor 4; Uterus

The mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway plays a key role in mediating estrogen actions in the brain and neuronal sensitization during inflammation. Estrogen status is a risk factor in chronic temporomandibular muscle/joint (TMJ) disorders; however, the basis for this relationship is not known. The present study tested the hypothesis that estrogen status acts through the MAPK/ERK signaling pathway to alter TMJ nociceptive processing. Single TMJ-responsive neurons were recorded in laminae I-II at the spinomedullary (Vc/C(1-2)) junction in naïve ovariectomized (OvX) female rats treated for 2 days with high-dose (20 microg/day; HE2) or low-dose estradiol (2 microg/day; LE2) and after chronic inflammation of the TMJ region by complete Freund's adjuvant for 12-14 days. Intra-TMJ injection of ATP (1 mM) was used to activate Vc/C(1-2) neurons. The MAPK/ERK inhibitor (PD98059, 0.01-1 mM) was applied topically to the dorsal Vc/C(1-2) surface at the site of recording 10 min prior to each ATP stimulus. In naïve HE2 rats, low-dose PD98059 caused a maximal inhibition of ATP-evoked activity, whereas even high doses had only minor effects on units in LE2 rats. By contrast, after chronic TMJ inflammation, PD98059 produced a marked and similar dose-related inhibition of ATP-evoked activity in HE2 and LE2 rats. These results suggested that E2 status and chronic inflammation acted, at least in part, through a common MAPK/ERK-dependent signaling pathway to enhance TMJ nociceptive processing by laminae I-II neurons at the spinomedullary junction region.

Topics: Adenosine Triphosphate; Animals; Chronic Disease; Dose-Response Relationship, Drug; Enzyme Activation; Estradiol; Estrogens; Female; Inflammation; Mitogen-Activated Protein Kinases; Neurons; Ovariectomy; Pain; Rats; Rats, Sprague-Dawley; Signal Transduction; Skin; Temporomandibular Joint; Trigeminal Caudal Nucleus

Activation of the alpha(2)-adrenoceptor has been shown to produce antinociception. We have previously shown that the antinociceptive effect of clonidine, an alpha(2)-adrenoceptor agonist, is sex-specific and is abolished by exogenous estrogen in ovariectomized rats or high level of endogenous estrogen in proestrous females. Here, we investigated whether testosterone mediates the antinociceptive effect of clonidine in the trigeminal region of the male rat. Clonidine (7 microg/5 microl) was injected intracisternally through a PE-10 cannula implanted dorsal to the trigeminal region in orchidectomized (GDX) male Sprague-Dawley rats. In separate groups, testosterone propionate (250 microg/100 microl; GDX+T) or beta-estradiol benzoate (100 microg/100 microl; GDX+E) were injected subcutaneously 24 and 48 h respectively prior to the N-methyl-D-aspartic acid (NMDA)--or heat-evoked nociceptive test. NMDA-induced number of scratches or duration of scratching behavior did not change significantly in control groups with or without hormonal replacement. Clonidine significantly reduced both measures only in the GDX+T group but not in GDX or GDX+E group. Clonidine also significantly increased head withdrawal latency (HWL) in the GDX+T group, but not in GDX or GDX+E group. The antinociceptive effect of clonidine was reversed by yohimbine, an alpha(2)-adrenoceptor antagonist, in GDX+T group. We conclude that testosterone is required for the expression of antinociception produced by selective activation of the alpha(2)-adrenoceptor in the trigeminal region of the male rat. These findings further our understanding of sex-related differences in the modulation of nociception and may provide insight into development and administration of analgesic agents in young vs. aging men.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Catheterization; Clonidine; Estradiol; Estrogens; Hormone Replacement Therapy; Hot Temperature; Male; N-Methylaspartate; Orchiectomy; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Testosterone; Testosterone Propionate; Time Factors; Trigeminal Nuclei; Yohimbine

Gonadal hormones may modulate analgesia responses induced by acute stress in humans and rats. To evaluate the effects of gonadal hormones in modifying neuropathic pain, we measured autotomy changes following sciatic nerve resection in ovariectomized rats and in the presence of estrogen replacement. Two groups of female rats were subjected to ovariectomy and sham surgery. Each group was then divided into two subgroups receiving subcutaneously sesame oil with or without estradiol benzoate (5 microg/day/rat). All rats then underwent sciatic nerve resection in one hindlimb. Degree of self-mutilation was measured daily for 8 weeks. Estradiol treatment resulted in significantly lower autotomy scores in ovariectomized rats (3.6 +/- 0.6 vs. 5.5 +/- 0.3, p < 0.01) and in sham-operated rats (3.4 +/- 0.7 vs. 5.1 +/- 0.4, p < 0.05). The results of this study indicate that estrogen can modify the autotomy behavior, an indicator of neuropathic pain, in rats after nerve injury.

Topics: Animals; Chronic Disease; Estradiol; Female; Ovariectomy; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Self Mutilation; Time Factors

Baseline nociception and opioid antinociception were compared in male and ovariectomized female rhesus monkeys. Females were studied without estradiol replacement or during treatment with estradiol benzoate at doses (0.002 and 0.01 mg/kg/day) designed to mimic 17beta-estradiol blood levels observed during different phases of the menstrual cycle and during pregnancy. Baseline sensitivity to thermal stimuli (42-54 degrees C) was similar in male and ovariectomized female monkeys. The antinociceptive effects of the mu-opioid agonists fentanyl, morphine, butorphanol, and nalbuphine were examined at 50 and 54 degrees C. There were no sex-related differences in the antinociceptive effects of the high-efficacy mu agonist fentanyl; however, the lower-efficacy mu agonists morphine, butorphanol, and nalbuphine produced greater antinociceptive effects in males than in untreated ovariectomized females. Because butorphanol and nalbuphine have low selectivity for mu versus kappa receptors and may produce kappa-agonist effects under some conditions, the high-efficacy, kappa-selective agonist U50,488 was also studied. U50,488 also produced greater antinociceptive effects in males. Treatment with estradiol benzoate tended to enhance opioid antinociception in the ovariectomized females; however, this effect was significant only for butorphanol and U50,488 during treatment with the highest dose of estradiol benzoate. These findings suggest that opioid agonists usually produce greater antinociception in male monkeys than in females, and the magnitude of these sex-related differences may be inversely related to efficacy at mu receptors or selectivity for mu versus kappa receptors. Estradiol appears to have little effect on mu-agonist antinociception in primates but may enhance the antinociceptive effects of kappa agonists.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Estradiol; Estrogen Replacement Therapy; Female; Hot Temperature; Macaca mulatta; Male; Nociceptors; Ovariectomy; Pain; Receptors, Opioid, kappa; Receptors, Opioid, mu; Sex Factors