PubMed · 15352643
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Getting comfortable with methadone.. https://pubmed.ncbi.nlm.nih.gov/15352643/
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The present study evaluated the effects of phenytoin (DPH) on the binding to synaptosomal fraction membranes from guinea pig brain of the prototypic sigma1 (sigma1) receptor agonist [3H](+)-pentazocine and the putative sigma1 antagonist [3H]NE-100. Equilibrium and binding kinetics studies were done. The order of affinity of 12 sigma1 ligands for binding sites labeled with [3H](+)-pentazocine correlated well with their order of affinity for sites labeled with [3H]NE-100, suggesting that both radioligands label the same receptor. Phenytoin increased the binding of [3H](+)-pentazocine, enhancing its affinity (K(D) value) for sigma1 receptors and decreasing its dissociation rate from these receptors. The maximal number of receptors (B(max) value) labeled with [3H](+)-pentazocine was not changed. In contrast, phenytoin decreased the specific binding and maximal number of receptors labeled with [3H]NE-100, and increased its dissociation rate from sigma1 receptors. The affinity of this radioligand for sigma1 receptors was not modified. In conclusion, phenytoin behaved as a positive allosteric modulator on the binding of [3H](+)-pentazocine, whereas it negatively modulated the binding of [3H]NE-100. These results add evidence in favor of the use of phenytoin in vitro to distinguish between agonists and antagonists of sigma1 receptors.
RATIONALE: The sex of the individual can have a profound effect on sensitivity to the effects of opioids. Recently, our laboratory provided the first evidence that females may be more sensitive to the immune-altering effects of mu-opioids than males. However, it remains unknown whether kappa- and delta-opioids produce sexually dimorphic effects on immune responses. OBJECTIVE: The present study sought to determine whether kappa- and delta-opioids produce differential immunological effects in males and females using the memory-T-cell-dependent in vivo inflammatory response contact hypersensitivity (CHS). As sex differences in the magnitude of opioid effects can be outcome-specific, additional experiments were conducted to compare the immunological effects of kappa- and delta-opioids with other behavioral and physiological effects. MATERIALS AND METHODS: Contact hypersensitivity was induced in male and female Fischer rats. Prior to elicitation of CHS, animals were administered selected doses of the kappa-opioid spiradoline (0.2-20 mg/kg), delta-opioid SNC80 (1-10 mg/kg), or vehicle. The antinociceptive and diuretic effects of spiradoline were also assessed in males and females, as were the locomotor effects of SNC80. RESULTS: Spiradoline produced significantly greater enhancement of CHS in females than males, but produced comparable antinociceptive and diuretic effects in both sexes. By contrast, SNC80 did not significantly affect the course of CHS in either sex, but females were significantly more sensitive to its locomotor stimulatory effects. CONCLUSIONS: These results demonstrate that females are more sensitive than males to the CHS-altering effects of spiradoline and that sex differences in the magnitude and direction of opioid-induced sex differences are outcome dependent.
The antinociception induced by i.t. or i.c.v. administration of endomorphins is mediated via mu-opioid receptors. However, although endomorphins do not have an appreciable affinity for kappa-opioid receptors, pretreatment with the kappa-opioid receptor antagonist norbinaltorphimine markedly reduces the antinociceptive response to i.c.v. or i.t. administered endomorphin-2 but not endomorphin-1. These results suggest that endomorphin-2 initially stimulates mu-opioid receptors, which subsequently induce the release of dynorphins that act on kappa-opioid receptors to produce antinociception. The present study was performed in mice to determine whether the release of dynorphins by i.t. administered endomorphin-2 is mediated through mu-opioid receptors to produce antinociception. Intrathecal pretreatment with an antiserum against dynorphin A-(1-17), but not against dynorphin B-(1-13) or alpha-neoendorphin, dose-dependently prevented the paw-withdrawal inhibition by endomorphin-2. The pretreatments with these antisera did not affect the endomorphin-1- or [D-Ala(2),MePhe(4),Gly(ol)(5)]enkephalin-induced paw-withdrawal inhibition. The attenuation of endomorphin-2-induced antinociception by i.t. pretreatment with an antiserum against dynorphin A-(1-17) or s.c. pretreatment with norbinaltorphimine was blocked dose-dependently by s.c. pretreatment with the mu-opioid receptor antagonist beta-funaltrexamine or the mu(1)-opioid receptor antagonist naloxonazine at ultra-low doses that are ineffective against mu-opioid receptor agonists. These results suggest that the spinal antinociception induced by endomorphin-2 is mediated through the stimulation of a distinct subtype of mu(1)-opioid receptor that induces the release of the endogenous kappa-opioid peptide dynorphin A-(1-17) in the spinal cord.