The effects of 17ß-oestradiol on increased α(1)-adrenergic vascular reactivity induced by prolonged ovarian hormone deprivation: the role of voltage-dependent L-type Ca channels.

The present study investigated the hypothesis that the duration of ovarian hormone deprivation before reintroduction of oestrogen affects the role of oestrogen as a mediator of the contractile function of α(1)-adrenergic receptors. Rats underwent ovariectomy (OVX) or were sham-operated, and the OVX rats were treated with vehicle (corn oil) or 17ß-oestradiol (E(2)) for 5 days either 10, 28 or 60 days after OVX. The OVX increased phenylephrine- and Ca(2+)-induced contractions. Interestingly, the phenylephrine-induced contractions were increased at each of the three time points, whereas the Ca(2+)-induced contractions were only increased in the 60-day group. E(2) had biphasic effects on phenylephrine- and Ca(2+)-induced contractility. Indeed, E(2) increased contractions in the 10-day group and diminished contractions in the other groups (the increased contractions were avoided by verapamil). These results indicate that E(2) controls α(1)-adrenergic receptor-mediated contractility through effects on L-type Ca(2+) channels in a way that depends on the timing in which the treatment with E(2) is initiated.

Formalin-induced long-term secondary allodynia and hyperalgesia are maintained by descending facilitation.

This work analyzes the role of cholecystokinin (CCK) receptors, dynorphin A1₋17 and descending facilitation originated in the rostral ventromedial medulla (RVM) on secondary allodynia and hyperalgesia in formalin-injected rats. Formalin injection (50 µL, 1%, s.c.) produced acute nociception (lasting 1 h) and long-term secondary allodynia and hyperalgesia in ipsilateral and contralateral hind paws (lasting 1-12 days). Once established, intra-RVM administration of lidocaine at day 6, but not at 2, reversed secondary allodynia and hyperalgesia in rats. The injection of YM022 (CCK2 receptor antagonist), but not lorglumide (CCK1 receptor antagonist), into the RVM or spinal cord reversed both nociceptive behaviors. Pre-treatment with lidocaine, lorglumide or YM022 did not prevent the development of secondary allodynia or hyperalgesia regardless of the administration route. Formalin injection increased dynorphin content in the dorsal, but not the ventral, spinal cord sections at day 6. Moreover, intrathecal administration of dynorphin antiserum reversed, but was unable to prevent, secondary allodynia and hyperalgesia in both hind paws. These results suggest that formalin-induced secondary allodynia and hyperalgesia are maintained by activation of descending facilitatory mechanisms which are dependent on CCK2 receptors located in the RVM and spinal cord. In addition, data suggest that spinal dynorphin A1₋17 and CCK play an important role in formalin-induced secondary allodynia and hyperalgesia.

Melatonin reduces formalin-induced nociception and tactile allodynia in diabetic rats.

The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral administration of melatonin (10-300 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. In addition, K-185 (a melatonin MT(2) receptor antagonist, 0.2-2 mg/kg, s.c.) completely blocked the melatonin-induced antinociception in diabetic rats, whereas that naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) and naltrindole (a selective delta opioid receptor antagonist, 0.5 mg/kg, s.c.), but not 5'-guanidinonaltrindole (a selective kappa opioid receptor antagonist, 1 mg/kg, s.c.), partially reduced the antinociceptive effect of melatonin. Given alone K-185, naltrexone, naltrindole or 5'-guanidinonaltrindole did not modify formalin-induced nociception in diabetic rats. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of melatonin (75-300 mg/kg) dose-dependently reduced tactile allodynia in diabetic rats. Both antinociceptive and antiallodynic effects were not related to motor changes as melatonin did not modify number of falls in the rotarod test. Results indicate that melatonin is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that melatonin MT(2) and delta opioid receptors may play an important role in these effects.

Analysis of the mechanism underlying the peripheral antinociceptive action of sildenafil in the formalin test.

The mechanism of the antinociceptive action of the phosphodiesterase 5 inhibitor, sildenafil, was assessed in the formalin test. Local peripheral ipsilateral, but not contralateral, administration of sildenafil (50-200 microg/paw) produced a dose-related antinociception during both phases of the formalin test. The local peripheral pretreatment with protein kinase G inhibitor peptide (PKG inhibitor, 0.01-1 microg/paw), charybdotoxin (large- and intermediate-conductance Ca2+-activated K+ channel blocker, 0.01-1 microg/paw), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-2 microg/paw), tolbutamide (ATP-sensitive K+ channel blocker, 12.5-50 microg/paw), and tetraethylammonium (non-selective voltage-dependent K+ channel blocker, 12.5-50 microg/paw), but not 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, inhibitor of guanylyl cyclase, 12.5-50 microg/paw) or saline, significantly diminished in a dose-dependent manner sildenafil-induced local peripheral antinociception. Given alone, local peripheral administration of inhibitors did not modify formalin-induced nociceptive behavior. Results suggest that sildenafil produces its local peripheral antinociceptive effect via activation of the cyclic GMP-PKG-K+ channel pathway.

Evidence for the role of alpha1D- and alpha1A-adrenoceptors in contraction of the rat mesenteric artery.

We investigated the alpha(1)-adrenoceptor subtype(s) involved in contraction of the isolated rat mesenteric artery by the use of the agonists noradrenaline (NA), phenylephrine (PHE), oxymetazoline (OXY), and methoxamine (MET), the competitive antagonists 8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-8-azaspiro(4.5)decane-7,9-dione dihydrochloride (BMY 7378) and 5-methylurapidil, and the alkylating agent chloroethylclonidine (CEC). Agonists showed the potency order NA> or =PHE>OXY>MET; pA(2) values for 5-methylurapidil and BMY 7378 were 7.74+/-0.11 and 8.72+/-0.28, respectively, while Schild slopes were not different than unity; alpha(1)-adrenoceptor alkylation with CEC showed a drastic decrease in maximal agonists-induced contraction and a shift to the right of about 46-, 122-, 2-, and 15-fold higher than controls for NA, PHE, OXY, and MET, respectively. Data suggest that alpha(1D)-adrenoceptors predominate for contraction in mesenteric artery of the Wistar rat, with a second population of alpha(1A)-adrenoceptors responding at high agonist concentrations.