Interactions among aging, gender, and gonadectomy effects upon morphine antinociception in rats.

In addition to age-related deficits in morphine antinociception in female rats, gender and gonadectomy differences have also been observed, with male rats displaying greater magnitudes of effects than females and castrated males. Since there are little data indicating how aging, gender, and gonadectomy interact in modulating morphine antinociception, the present study evaluated alterations in this response as functions of age (6, 12, 18, and 24 months), gender, and gonadal status (intact, gonadectomized) across a dose range (1-10 mg/kg) and time course (0.5-2 h) on the tail-flick test.

Characterization of pituitary mediation of stress-induced antinociception in rats.

Antinociception, induced by continuous cold-water swims (CCWS) and certain parameters of inescapable foot shock, is reduced in hypophysectomized rats receiving supplements of corticosterone and l-thyroxine. To assess which lobe of the pituitary gland is involved in this effect, the first experiment compared the effects of total hypophysectomy and posterior lobectomy in supplemented rats upon CCWS antinociception on the tail-flick and jump tests and upon continuous inescapable foot shock antinociception on the tail-flick test. Total hypophysectomy, but not posterior lobectomy, significantly reduced CCWS antinociception on both tests in supplemented rats relative to sham surgery.

Involvement of mu1 and mu2 opioid receptor subtypes in tail-pinch feeding in rats.

Tail-pinch feeding (TPF) in rats is decreased following general (naltrexone, NTX) and mu (Cys2-Tyr3-Orn5-Pen7-amide, CTOP) opioid antagonists, but not following kappa (nor-binaltorphamine. Nor-BNI) or delta (naltrindole, NTI) opioid antagonists. Because multiple mu (mu1 and mu2) and delta (delta 1 and delta 2) opioid receptor subtypes have been characterized, the present study evaluated whether TPF was differentially altered following ICV administration of general (NTX), mu (beta-funaltrexamine, B-FNA), mu1 (naloxonazine, NAZ), kappa (Nor-BNI), delta 1 ([D-Ala2, Leu5, Cys6]-enkephalin, DALCE) and delta 2 (NTI) opioid antagonists.

Serotonin receptor subtype antagonists in the medial ventral medulla inhibit mesencephalic opiate analgesia.

Supraspinal opioid analgesia is mediated in part by connections between the midbrain periaqueductal gray (PAG) and the ventral-medial medulla, including the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis (NRGC). A serotonergic synapse appears to participate in this pathway since methysergide microinjected into the NRM-NRGC significantly reduced morphine analgesia elicited from the PAG. The present study evaluated the role of specific serotonin receptor subtypes by pretreating rats with microinjections of either the 5HT2 antagonist, ritanserin or the 5HT3 antagonist, ICS205930, into the NRM-NRGC and examining their effects upon morphine (2.

2-Deoxy-D-glucose antinociception and serotonin receptor subtype antagonists: test-specific effects in rats.

The antinociceptive actions of 2-deoxy-D-glucose (2-DG) are mediated in part by endogenous opioid, dopaminergic, cholinergic, histaminergic, and neurohormonal influences. Although 2-DG antinociception was not affected by tryptophan hydroxylase inhibition, a possible serotonergic role in 2-DG antinociception was investigated because of the existence of serotonin [5-hydroxytryptamine (5-HT)] receptor subtypes. The present study examined the effects of general (methysergide: 5 and 10 mg/kg), 5-HT2 (ritanserin: 2.

Central opioid receptor subtype antagonists differentially alter sucrose and deprivation-induced water intake in rats.

The present study compared the effectiveness of centrally-administered opioid receptor subtype antagonists to inhibit intake of either a 10% sucrose solution under ad libitum conditions, or water following 24 h of water deprivation. Full dose-response functions were evaluated over a 1 h period for the following antagonists: naltrexone (general: 1-50 micrograms), nor-binaltorphamine (Nor-BNI, kappa: 1-20 micrograms), beta-funaltrexamine (beta-FNA, mu: 1-20 micrograms), naltrindole (delta 2: 1-20 micrograms), [D-Ala2, Leu5, Cys6]-enkephalin (DALCE, delta 1: 10-40 micrograms) and naloxonazine (mu 1: 10-50 micrograms). Naltrexone significantly and dose-dependently inhibited both sucrose intake (64-67%) and deprivation-induced water intake (53-67%).

Naltrexone, serotonin receptor subtype antagonists, and glucoprivic intake: 2. Insulin.

Opiate antagonist inhibition of deprivation-induced intake and 2-deoxy-D-glucose (2DG) hyperphagia is significantly enhanced by the 5-hydroxytryptamine3 (5-HT3) antagonist, ICS-205,930. Interactions between opiate antagonists and either 5-HT or 5-HT2 antagonists produced smaller effects. The present study evaluated whether insulin (5 U/kg) hyperphagia was affected by methysergide (0.

Naltrexone, serotonin receptor subtype antagonists, and glucoprivic intake: 1. 2-Deoxy-D-glucose.

Inhibition of deprivation-induced intake by naloxone was significantly enhanced by the 5-hydroxytryptamine3 (5-HT3) antagonist ICS-205,930. Interactions between naloxone and either the general 5-HT antagonist methysergide or the 5-HT2 antagonist ritanserin or ketanserin produced smaller effects. The present study evaluated whether 2-deoxy-D-glucose (2DG, 400 mg/kg) hyperphagia was affected by methysergide (0.

Naloxone benzoylhydrazone, a kappa 3 opioid agonist, stimulates food intake in rats.

Naloxone benzoylhydrazone (NalBzoH) is a selective, short-acting agonist at the kappa 3 opioid receptor and a slowly dissociating potent antagonist at the mu opioid receptor. Given the important role of kappa receptors in the opioid control of food intake, the present study examined the central and peripheral effects of NalBzoH upon food intake. Central administration of NalBzoH (1-20 micrograms, i.

Potentiation of 2-deoxy-D-glucose antinociception, but not hyperphagia by zolantidine, a histamine (H2) receptor antagonist.

Antagonism of the histamine (H2) receptor reduces antinociception induced by naloxone-resistant foot-shock, naloxone-sensitive foot-shock, and morphine with a rank-order potency similar to their H2 antagonism. The antimetabolic glucose analog 2-deoxy-D-glucose (2DG) produces antinociceptive and hyperphagic responses that dissociate from each other and are in part mediated by opioid systems. The present study determined the effects of the brain-penetrating H2 receptor antagonist zolantidine (ZOL) on 2DG antinociception on the tail-flick and jump tests, as well as on 2DG hyperphagia, in rats.

Roles of gender and gonadectomy in pilocarpine and clonidine analgesia in rats.

Central and systemic morphine analgesia as well as both opioid and nonopioid forms of swim analgesia display gender differences with male rats showing greater magnitudes of analgesia than female rats. Since nonopioid swim analgesia is dependent upon muscarinic cholinergic and alpha 2-noradrenergic mechanisms, the present study evaluated in rats whether gender, adult gonadectomy or estrous phase altered analgesia induced by either the muscarinic cholinergic receptor agonist, pilocarpine or the alpha 2-noradrenergic receptor agonist, clonidine. Pilocarpine (1-10 mg/kg) analgesia was significantly greater in male rats.

Endopeptidase 24.15 inhibition and opioid antinociception.

Whereas endopeptidase 24.11 cleaves the Gly-Phe bond in both Met- and Leu-enkephalin, endopeptidase 24.15 rapidly converts dynorphin A1-8, alpha and beta-neoendorphin into Leu-enkephalin, and Met-enkephalin-Arg6-Gly7-Leu8 (MERGL) into Met-enkephalin.

Inhibition of mesencephalic morphine analgesia by methysergide in the medial ventral medulla of rats.

The neural substrates of endogenous supraspinal opioid pain inhibition are mediated in part by connections between the midbrain periaqueductal gray (PAG) and the ventral-medial medulla, including the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis (NRGC). To ascertain whether a serotonergic synapse participated in this pathway, the present study determined whether microinjections of methysergide into the NRM or NRGC would alter analgesia elicited by morphine microinjections into the PAG. Morphine (2.

Increases in opioid-mediated swim antinociception following endopeptidase 24.15 inhibition.

The duration of action and potency of endogenous opioid peptides are limited by proteolytic enzymes such as endopeptidases 24.11 and 24.15.

Synergistic analgesic interactions between the periaqueductal gray and the locus coeruleus.

Opiates modulate pain perception at a number of different levels within the central nervous system and the importance of synergistic spinal and supraspinal influences have been well documented. In the present study we demonstrate synergistic interactions between the periaqueductal gray and locus coeruleus. Administered either systemically or intracerebroventricularly (i.

Differential actions of central alloxan upon opioid and nonopioid antinociception in rats: a further examination.

Previous work demonstrated that central pretreatment with alloxan significantly reduced antinociception induced by morphine and 2-deoxy-D-glucose (2DG), an opioid-mediated stressor, but not induced by continuous cold-water swims (CCWS), a nonopioid-mediated stressor. The alloxan-induced deficits in 2DG antinociception were ameliorated by coadministration of D-glucose (3 M, 3M-DG). The present study evaluated this relationship further by: a) examining whether central alloxan reduced morphine antinociception following either simultaneous 3M-DG and alloxan coadministration, alloxan followed 10 days later by 3M-DG and 3M-DG alone, and b) determining whether central alloxan pretreatment altered nonopioid antinociception induced by the muscarinic cholinergic agonist, pilocarpine.

Ingestive behavior following central [D-Ala2, Leu5, Cys6]-enkephalin (DALCE), a short-acting agonist and long-acting antagonist at the delta opioid receptor.

DALCE (1-40 micrograms, ICV), a short-acting agonist and long-acting antagonist at the delta opioid receptor, was examined for its effects upon food intake in rats under spontaneous, deprivation, glucoprivic and palatable conditions. DALCE (10 micrograms) significantly stimulated free feeding for up to 10 h but only minimally decreased (40 micrograms) food intake and body weight after 24-72 h. DALCE, administered prior to food deprivation (24 h), failed to affect subsequent 24-h intake and sporadically decreased intake and body weight change after 48-72 h.

Mediation of insulin hyperphagia by specific central opiate receptor antagonists.

The hyperphagic properties of insulin (10 U/kg, s.c.) were transiently (2h) and dose-dependently inhibited (30%) by central pretreatment with naltrexone (20-50 micrograms, i.

Gender effects and central opioid analgesia.

Central morphine analgesia is significantly greater in male than in female rats. Since mu and delta opioid receptor subtypes have been implicated in supraspinal analgesia, the present study evaluated whether gender or adult gonadectomy altered (a) analgesia on the tail-flick and jump tests following central administration of the mu-selective agonist, [D-Ala2, Me-Phe4, Gly(ol)5] enkephalin (DAMGO) and the delta-selective agonist, [D-Ser2,Leu5] enkephalin-Thr6 (DSLET) and (b) mu1, mu2 and delta opioid receptor binding. Sham-operated male rats displayed significantly greater magnitudes of peak and total analgesia than sham-operated females on the tail-flick test following DAMGO, but not DSLET.

Naloxone and serotonin receptor subtype antagonists: interactive effects upon deprivation-induced intake.

Whereas opiate receptor antagonists generally act to inhibit food intake under a variety of physiological conditions in rats, agonists of some serotonin (5-HT) receptor subtypes appear to stimulate intake, and others appear to inhibit intake. The present study evaluated the effects of the general 5-HT receptor antagonist, methysergide (1-5 mg/kg), the 5-HT2 receptor antagonists, ketanserin (1-2.5 mg/kg) and ritanserin (1-2.

Antinociceptive properties of inhibitors of endopeptidase 24.15.

Endopeptidase 24.15, a metalloendopeptidase active in brain, rapidly converts prodynorphin-derived peptides into leu-enkephalin. Inhibitors of this enzyme slow the degradation of these peptides in vivo and in vitro.

Reduction by central beta-funaltrexamine of food intake in rats under freely-feeding, deprivation and glucoprivic conditions.

The present study evaluated the central effects of beta-funaltrexamine (B-FNA), a non-equilibrium antagonist of mu-opioid receptors and a reversible agonist of kappa-opioid receptors upon food intake in rats under freely-feeding, deprivation and glucoprivic conditions. B-FNA elicited distinct short-term and long-term actions, consistent with binding studies demonstrating its reversible kappa agonist actions and its irreversible mu receptor blockade. Whereas B-FNA (1-20 micrograms, i.

Suppression of nocturnal, palatable and glucoprivic intake in rats by the kappa opioid antagonist, nor-binaltorphamine.

The increased food intake in the rat during the first two hours of the dark cycle was significantly inhibited by central pretreatment with either the selective kappa opioid antagonist, nor-binaltorphamine (NorBNI, 20 micrograms, i.c.v.

Blockade of morphine analgesia by both pertussis and cholera toxins in the periaqueductal gray and locus coeruleus.

Rats demonstrating analgesia following microinjection of morphine into the periaqueductal gray (PAG) or locus coeruleus (LC) were injected with either pertussis toxin, cholera toxin or saline into the same brain region. Both pertussis and cholera toxin blocked the analgesic effect of morphine at both injection sites for up to 7 days after toxin treatment. These results indicate that morphine analgesia is a complex response involving systems dependent upon Gs as well as Gi or Go proteins.