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.

Proglumide selectively potentiates supraspinal mu 1 opioid analgesia in mice.

The cholecystokinin antagonist proglumide potentiates morphine analgesia. To understand more fully the opiate receptor subtypes involved with this effect, we investigated the effect of proglumide on spinal and supraspinal mu and spinal delta analgesia in mice. Proglumide alone had no effect on tailflick latencies, but increased, in a dose-dependent manner, tailflick latencies in morphine-tolerant mice.

Inhibition of deprivation-induced feeding by naloxone and cholecystokinin in rats: effects of central alloxan.

Central administration of alloxan reduces the hyperphagic, but not the hyperglycemic response to glucoprivation by presumably acting upon brain glucoreceptors or a glucoprivic control mechanism. The present study evaluated whether central alloxan pretreatment respectively altered the dose-dependent suppressant effects upon deprivation (24-hr)-induced feeding of naloxone (0.01-10 mg/kg, IP) and cholecystokinin octapeptide (CCK-8: 1-8 micrograms/kg, IP) in rats.

Selective opioid receptor antagonist effects upon intake of a high-fat diet in rats.

Short-term (2 h) intake of a high-fat diet in rats was significantly inhibited by intravenous (0.1-10 mg/kg: 39-67%) and central (1-5 micrograms, i.c.

Antagonism of morphine analgesia by nonopioid cold-water swim analgesia: direct evidence for collateral inhibition.

The demonstrated existence of opioid and nonopioid forms of pain control has raised questions as to how they interact. Previous indirect evidence suggests that activation of one system inhibited the activation of the other. The present study assessed this directly using morphine as an opiate form of analgesia and continuous cold-water swims (CCWS, 4 degrees C, 2 min) as the nonopioid form.

Effects of opioid peptides on peripheral stimulation and "stress"-induced analgesia in animals.

This review has established the basis for an opiate pain-inhibitory system as well as pharmacological and physiological evidence suggesting alternative nonopiate systems. The concept of multiple forms of pain inhibition became apparent through the study of stress-induced analgesia and the classification of effects across opioid/nonopioid and neural/neurohormonal dimensions. These effects were compared with traditional pathways identified for opiate pain inhibition, and the use of other environmental forms of analgesia (cervical probing, defeat) were explored similarly.

Mediation of anorexia by human recombinant tumor necrosis factor through a peripheral action in the rat.

Human recombinant tumor necrosis factor (TNF) produces significant anorexia in the rat which persists for up to 24 h after a single dose (5 micrograms/325 g rat). Dose-response studies indicate similar potencies for TNF following central or peripheral administration. Brain 125I-TNF levels were more than 100-fold greater after intracerebroventricular than i.

Differential actions of central alloxan upon opioid and nonopioid antinociception in rats.

Spontaneous or induced diabetes, as well as glucose loading, reduce opiate antinociception, presumably through induction of hyperglycemia. While peripheral administration of alloxan is a potent pancreatic beta-cell toxin, intracerebroventricular (ICV) alloxan reduces glucoprivic feeding in the absence of hyperglycemia, presumably through interactions with specific brain glucoreceptors. Our laboratory demonstrated that opioid-mediated 2-deoxy-D-glucose (2DG) antinociception is significantly reduced by central pretreatment with alloxan, and that this deficit is reversed by coadministration with 3M-D-glucose.

Reduction in opioid and non-opioid forms of swim analgesia by 5-HT2 receptor antagonists.

Acute exposure to continuous (CCWS) or intermittent (ICWS) cold-water swims elicits non-opioid and opioid forms of analgesia respectively. Intrathecal administration of methysergide blocks ICWS, but not CCWS analgesia. The present study evaluated the role of serotonin (5-HT) receptor subtypes in the mediation of CCWS and ICWS analgesia on the tail-flick and jump tests following administration of methysergide, a non-specific 5-HT antagonist and pirenpirone and ketanserin, two 5-HT2 receptor subtype antagonists.

Different mu receptor subtypes mediate spinal and supraspinal analgesia in mice.

To examine the relative roles of mu 1- and mu 2-receptors in spinal and supraspinal analgesia, we assessed the effects of naloxonazine, naloxone, beta-funaltrexamine (beta-FNA), and ICI-154,129 on tail-flick analgesia produced by intrathecal or intracerebroventricular injections of the highly mu-selective agonist, [D-Ala2,Me-Phe4,Gly(ol)5]enkephalin (DAGO; mu 1 and mu 2), [D-Ser2,Leu5]enkephalin-Thr6 (DSLET; mu 1 and delta), and the selective delta-receptor agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) in mice. Both DAGO and DSLET supraspinal analgesia were mediated through mu 1-receptors. Naloxonazine shifted the supraspinal DAGO dose-response curve 4-fold to the right without changing the curve for spinal DAGO.

Roles of gender, gonadectomy and estrous phase in the analgesic effects of intracerebroventricular morphine in rats.

Gender and gonadal function have previously been shown to influence the magnitude of analgesia following systemic morphine and opioid and nonopioid forms of swim analgesia with male rats displaying greater analgesia than female rats and gonadectomy reducing analgesic magnitude in both genders. These effects have been presumed to be centrally mediated. The present study evaluated the roles of gender, gonadectomy and estrous phase upon dose-response and time-response functions of analgesia following intracerebroventricular administration of morphine as measured by the tail-flick and jump tests.

Dissociation of opioid and nonopioid analgesic responses following adult monosodium glutamate pretreatment.

Neonatal administration of monosodium glutamate (MSG: 2-4 mg/g, SC) selectively destroys circumventricular organs, especially the arcuate nucleus and median eminence of the hypothalamus, and also attenuates both nonopioid (continuous cold-water swim: CCWS) and opioid (morphine) analgesia when rats are tested as adults. The present study evaluated whether administration of MSG (1-6 g/kg, SC) or its equiosmotic control (2.37 M NaCl) to adult rats altered either basal nociception on the tail-flick and jump tests or analgesia following morphine (5 mg/kg, SC) or CCWS (2 degrees C for 3.

Post-natal morphine differentially affects opiate and stress analgesia in adult rats.

Alterations in nociceptive reactivity, opiate receptor binding, and other behavioral responses occur in rats exposed to morphine either in utero or post-natally. The present study examined whether post-natal morphine (0, 1 or 20 micrograms, days 1-7) altered analgesia on the tail-flick and jump tests induced by nonopioid-mediated continuous cold-water swims (CCWS), opioid-mediated intermittent cold-water swims (ICWS) or morphine (2.5 and 5.

Organismic variables and pain inhibition: roles of gender and aging.

Multiple pain-inhibitory systems dependent upon both opioid and nonopioid mechanisms of action have been identified, particularly in the rodent. The experimental subject has typically been the young, adult male rat, and generalizations concerning these systems have been made from this subject pool. This review focuses upon the roles of two organismic factors, aging and gender, in the modulation of analgesic processes.

Potentiation of opioid and nonopioid forms of swim analgesia by cimetidine.

Antagonism of the H-2 receptor with cimetidine and other histaminergic receptor antagonists has been used to differentiate nonopioid and opioid forms of footshock analgesia which are mediated by neural mechanisms. Cimetidine reduces nonopioid footshock analgesia while potentiating an opioid form of this analgesia. The present study examined whether cimetidine altered the nonopioid, neurohormonal analgesia induced by either continuous cold-water swims (CCWS: 2 degrees C for 3.

Role of mu 1-opiate receptors in supraspinal opiate analgesia: a microinjection study.

Microinjection of opiates into either the periaqueductual gray, locus coeruleus, nucleus raphe magnus, or nucleus reticularis gigantocellularis elicits a profound naloxone-sensitive analgesia. mu-Opioid receptors have been implicated in supraspinal analgesia and studies from our laboratory have demonstrated the importance of the mu 1-receptor subtype. In an effort to examine the receptor subtypes responsible for opioid analgesia in specific brain regions, we examined dose-response relationships and naloxonazine sensitivity of morphine and two enkephalin derivatives in the above 4 brain regions.

Comparison of effects of chronic administration of naloxone and naloxonazine upon food intake and maintainance of body weight in rats.

A comparison of the effects of the short-acting opioid antagonist naloxone, with the irreversible and highly-specific mu-1 antagonist naloxonazine, has categorized the mediation of opioids in some forms of feeding into mu-1 and non-mu-1 components. The mu-1 sites have been implicated in free-feeding, deprivation-induced feeding and morphine-induced hyperphagia, based upon their sensitivity to both naloxone and naloxonazine. However, the ability of naloxone, but not naloxonazine to inhibit feeding, induced by either 2-deoxy-D-glucose glucoprivation, ethylketocyclazocine, dynorphin or (D-ala2.

Gender determinants of opioid mediation of swim analgesia in rats.

Continuous cold-water swims (CCWS) and intermittent cold-water swims (ICWS) elicit respective nonopioid and opioid analgesic responses in adult male rats. The present experiment evaluated whether gender differences were observed in naloxone's (14 mg/kg, SC) ability to alter differentially CCWS and ICWS analgesia on the tail-flick and jump tests in age-matched and weight-matched intact rats and in gonadectomized rats. CCWS analgesia was unaffected by naloxone on either test in age-matched males and females.

Irreversible opiate agonists and antagonists. IV. Analgesic actions of 14-hydroxydihydromorphinone hydrazones.

Several phenylhydrazone derivatives of oxymorphone [phenylhydrazone and p-nitrophenylhydrazone (OxyPNPH)] as well as oxymorphonazine produce a wash-resistant inhibition of radiolabeled opioid binding, suggesting nonequilibrium binding to opiate receptors. All are agonists and, in an effort to correlate their prolonged inhibition of binding with their pharmacology, we examined their analgesic actions in vivo. Dose-response curves at 1 hr revealed similar potencies of oxymorphone and the derivatives, with the exception of OxyPNPH which was significantly less potent.

Intracerebroventricular alloxan reduces 2-deoxy-D-glucose analgesia.

2-Deoxy-D-glucose (2DG) analgesia, mediated in part by endogenous opiate and hypothalamo-hypophysial systems is presumably activated by its stress-related properties. Recently 2DG hyperphagia, but not 2DG hyperglycemia was reduced by central pretreatment with the pancreatic beta-cell toxin, alloxan; this deficit was eliminated by co-administration of 3M D-glucose. The present experiment examined whether intracerebroventricular pretreatment with alloxan (40 or 200 micrograms) altered 2DG analgesia (400 or 700 mg/kg, IP) on the tail-flick and jump tests, and whether 3M D-glucose co-administration ameliorated any deficits.

Yohimbine potentiates cold-water swim analgesia: re-evaluation of a noradrenergic role.

Continuous cold-water swims (CCWS) elicit a nonopioid and neurohormonal analgesia which displays adaptation. The norepinephrine (NE) system has been implicated since parallel alterations in NE occur following acute and repeated CCWS exposure, and since CCWS analgesia is reduced by locus coeruleus lesions and is potentiated by clonidine and desipramine. The present study evaluated the effects of the alpha-2 NE receptor antagonist, yohimbine upon CCWS (2 degrees C for 3.

Gender-specific and gonadectomy-specific effects upon swim analgesia: role of steroid replacement therapy.

Both gender-specific and gonadectomy-specific effects have been observed for the analgesic responses following continuous and intermittent cold-water swims (CCWS and ICWS respectively): female rats display significantly less analgesia than males, and gonadectomized rats display significantly less analgesia than sham-operated controls. The present study evaluated the effects of steroid replacement therapy with testosterone propionate (TP: 2 mg/kg, SC) upon CCWS and ICWS analgesia on the tail-flick and jump tests and hypothermia in sham-operated or gonadectomized male and female rats. Thirty days following surgery, rats received either no treatment, a sesame oil vehicle or TP for 14 days prior to, and then during testing.

Differential sensitivity of opioid-induced feeding to naloxone and naloxonazine.

The high-affinity mu-1 opioid binding site has been implicated in some opioid responses (e.g., supraspinal analgesia) but not others (e.

Loss of striatal mu1 opiate binding by substantia nigra lesions in the rat.

Opiate receptors have been identified within the striatum and some have been localized presynaptically to nigrostriatal neurons. Using unilateral ablative lesions of the substantia nigra, we examined binding in the ipsilateral and contralateral striata. Lesions significantly lowered both 3H[D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAGO) and 3H[D-Ala2,Leu5]enkephalin (DADL) binding.