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Biomedical subjects

T C Kirkham

Publications and source records attributed to T C Kirkham.

At least 19 recordsLinked to original sources
PubMed2006

Therapeutic potential of targeting the endocannabinoids: implications for the treatment of obesity, metabolic syndrome, drug abuse and smoking cessation.

Rimonabant (SR141716, Acomplia) has been described as an antagonist/inverse agonist at the cannabinoid receptor type 1 (CB1). It has been widely used as a tool to evaluate the mechanisms by which cannabinoid agonists produce their pharmacological effects and to elucidate the respective physiological or pathophysiological roles of the CB1 receptor. It has become increasingly clear that rimonabant can exert its own intrinsic actions. These may be viewed as evidence of either the inverse agonist nature of rimonabant or of tonic activity of the endocannabinoid system. To date, data obtained from clinical trials (RIO North America, RIO Europe and RIO Lipid) indicate that rimonabant may have clinical benefits in relation to its anti-obesity properties and as a novel candidate for the treatment of metabolic and cardiovascular disorders associated with overweight and obesity. Other clinical trials, such as the STRATUS study, have also shown that rimonabant may be effective in smoking cessation, and that the drug has a reasonable safety profile. Recently, it has been shown that rimonabant prevents indomethacin-induced intestinal injury by decreasing the levels of pro-inflammatory cytokine tumour necrosis factor alpha (TNFalpha), thus indicating that CB1 receptor antagonists might exhibit potential anti-inflammatory activity in acute and chronic diseases.

Animals↗
PubMed2006

Endocannabinoids in appetite control and the treatment of obesity.

Research into the endocannabinoid 'system' has grown exponentially in recent years, with the discovery of cannabinoid receptors and their endogenous ligands, such as anandamide and 2-arachidonoylglycerol (2-AG). Important advances have been made in our understanding of endocannabinoid transduction mechanisms, their metabolic pathways, and of the biological processes in which they are implicated. A decade of endocannabinoid studies has promoted new insights into neural regulation and mammalian physiology that are as revolutionary as those arising from the discovery of the endogenous opioid peptides in the 1970s. Thus, endocannabinoids have been found to act as retrograde signals: released by postsynaptic neurons, they bind to presynaptic heteroceptors to modulate the release of inhibitory and excitatory neurotransmitters through multiple G-protein-coupled receptor (GPCR)-linked effector mechanisms. The metabolic pathways of anandamide and 2-AG have now been been characterised in great detail, and we can anticipate that these pathways -- together with endocannabinoid uptake mechanisms -- will complement cannabinoid receptors as targets for the pharmacological analysis of the physiological functions of these substances. Specific insights into the potential role of endocannabinoid-CB1 receptor systems in central appetite control, peripheral metabolism and body weight regulation herald the clinical application of CB1 receptor antagonists in the management of obesity and its associated disorders.

Animals↗
PubMed2005

Endocannabinoids in the regulation of appetite and body weight.

The discovery of cannabinoid receptors, together with the development of selective cannabinoid receptor antagonists, has encouraged a resurgence of cannabinoid pharmacology. With the identification of endogenous agonists, such as anandamide, scientists have sought to uncover the biological role of endocannabinoid systems; initially guided by the long-established actions of cannabis and exogenous cannabinoids such as delta9-tetrahydrocannabinol (THC). In particular, considerable research has examined endocannabinoid involvement in appetite, eating behaviour and body weight regulation. It is now confirmed that endocannabinoids, acting at brain CB1 cannabinoid receptors, stimulate appetite and ingestive behaviours, partly through interactions with more established orexigenic and anorexigenic signals. Key structures such as the nucleus accumbens and hypothalamic nuclei are sensitive sites for the hyperphagic actions of these substances, and endocannabinoid activity in these regions varies in relation to nutritional status and feeding expression. Behavioural studies indicate that endocannabinoids increase eating motivation by enhancing the incentive salience and hedonic evaluation of ingesta. Moreover, there is strong evidence of an endocannabinoid role in energy metabolism and fuel storage. Recent developments point to potential clinical benefits of cannabinoid receptor antagonists in the management of obesity, and of agonists in the treatment of other disorders of eating and body weight regulation.

Animals↗
PubMed2001

Synergistic efects of opioid and cannabinoid antagonists on food intake.

RATIONALE: Central cannabinoid systems have been implicated in appetite regulation through the hyperphagic effects of exogenous and endogenous cannabinoids. These effects may involve activation of reward systems and be mediated in part by opioidergic processes. OBJECTIVE: Cannabinoid-opioid interactions in feeding were examined by testing the combined effects on food intake of sub-anorectic doses of selective antagonists for CB1 and opioid receptors. METHODS: Male rats (n = 8) received subcutaneous injections of naloxone (0, 0.1, 0.5, 1.0 mg/kg) and SR141716 (0, 0.1, 0.5, 1.0 mg/kg) before l-h, nocturnal food (chow) intake tests. RESULTS: Neither naloxone nor SR141716 reliably affected feeding when administered alone. By contrast, combined administration of the two antagonists significantly suppressed chow intake at each dose combination. Joint administration of the highest doses of each antagonist suppressed intake by 73%, a significantly greater effect than produced by either naloxone (32%) or SR141716 alone (17%). CONCLUSION: The data reveal a synergistic interaction between the effects of naloxone and SR141716 on feeding, provide further evidence of important functional relationships between endogenous cannabinoid and opioid systems, and strengthen the postulated role for endocannabinoids in reward processes contributing to the normal control of appetite.

Animals↗
PubMed1999

Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors.

RATIONALE: Central cannabinoid systems have been implicated in appetite regulation by the respective hyperphagic actions of exogenous cannabinoids, such as delta9-THC, and hypophagic effects of selective cannabinoid receptor antagonists. OBJECTIVE: This study examined whether an endogenous cannabinoid, anandamide, could induce overeating, via a specific action at central (CB1) cannabinoid receptors. METHODS: Pre-satiated male rats (n=18), received subcutaneous injections of anandamide (0.5, 1.0, 5.0, 10.0 mg/kg) before 3-h, nocturnal food intake tests. In a second series of intake tests (n=8), anandamide injection (1.0 mg/kg) was preceded by injection of the specific CB1 receptor antagonist, SR141716 (0.1, 0.5, 1.0 mg/kg SC). RESULTS: All doses of anandamide induced significant overeating, with 1.0 mg/kg being most potent. Additionally, hyperphagia induced by 1.0 mg/kg anandamide was dose-dependently attenuated by SR141716 pretreatment. CONCLUSION: This first demonstration of anandamide-induced, CB -mediated, overeating provides important evidence for the involvement of a central cannabinoid system in the normal control of eating.

Animals↗
PubMed1999

Diet-induced enhancement of naloxone sensitivity is independent of changes in body weight.

Intake of palatable solutions can enhance the anorectic potency of opioid antagonists. This experiment examined the relative contributions of orosensory experience and body weight gain to the enhanced anorectic potency of naloxone (0.125, 0.25, 0.5, and 1.0 mg/kg i.p.). Four groups of male hooded Lister rats (Charles River) were maintained on separate feeding regimes for 3 months. S-ADLIB rats were nondeprived with free access to lab chow and 20% (w/v) sucrose solution. S-RESTRICT rats received limited sucrose (50 ml/day) and chow (15 g/day) access, yoking their body weights to ADLIB rats receiving free access to lab chow only. RESTRICT rats received approx. 15 g of chow/day to maintain their body weights at 90% of the ADLIB rats. Fifteen-minute sucrose intake tests revealed marked differences between naloxone sensitivity of chronic sucrose drinkers and sucrose-naive groups. Intakes of S-ADLIB and S-RESTRICT were suppressed at all doses (max suppression >60%). In comparison to animals given sucrose, ADLIB and RESTRICT animals were significantly less sensitive (maximum suppression = 35%). Naloxone potency was independent of body weight differences. The data demonstrate that overconsumption of palatable ingesta, and not diet-induced weight gain, is sufficient to enhance antagonist potency. The study confirms that orosensory stimulation can induce plasticity in opioid systems, supporting an important role for opioids in intake regulation and general reward processes.

Animals↗
PubMed1998

Hyperphagia in pre-fed rats following oral delta9-THC.

Using a pre-feed paradigm, the effects of orally-administered delta9-tetrahydrocannabinol (THC) on low baseline levels of nocturnal feeding were assessed. Following 2-h access to a palatable wet mash diet at dark onset, adult male Lister hooded rats (Charles River) were treated with either sesame seed oil vehicle or delta9- tetrahydrocannabinol (0.063, 0.12, 0.25, 0.5, 1.0, or 2.0 mg/kg). One hour later, rats were allowed ad libitum access to standard chow, and intakes were monitored over the subsequent 24 h. Doses of 0.5, 1.0, and 2.0 mg/kg produced substantial hyperphagia during the first hour of testing. Subsequently, rats compensated for their overconsumption so that 24-h intakes were similar in all conditions. The data confirm anecdotal reports of the orexigenic actions of exogenous cannabinoids and suggest a critical role for endogenous cannabinoid systems in the regulation of appetite.

Administration, Oral↗
PubMed1995

Selective actions of central mu and kappa opioid antagonists upon sucrose intake in sham-fed rats.

Intake of a palatable sucrose solution in real-fed rats is mediated in part by central mu and kappa opioid receptors. Since general opioid antagonists still inhibit sucrose intake in sham-fed rats, the present study examined whether centrally administered mu (beta-funaltrexamine: 5, 20 micrograms), mu1 (naloxonazine: 50 micrograms), kappa (nor-binaltorphamine: 1, 5, 20 micrograms), delta (naltrindole: 20 micrograms) or delta 1 (DALCE: 40 micrograms) opioid subtype antagonists altered sucrose intake in sham-fed rats in a similar manner to systemic naltrexone (0.01-1 mg/kg) and whether such effects were equivalent to altering the sucrose concentration. Sucrose (20%) intake in sham-fed rats was significantly and dose-dependently reduced by naltrexone (59%), beta-funaltrexamine (44%) and nor-binaltorphamine (62%), but not by naloxonazine, naltrindole or DALCE. The reductions in sham sucrose (20%) intake by general, mu and kappa antagonism were similar in pattern and magnitude to diluting sucrose concentration from 20% to 10% in untreated sham-fed rats. Since both real-fed and sham-fed rats share similar patterns of specificity of opioid effects, magnitudes and potencies of inhibition, it suggests that central mu and kappa antagonism acts on orosensory mechanisms supporting sucrose intake.

Animals↗
PubMed1995

Prefeeding potentiates anorectic actions of neuromedin B and gastrin releasing peptide.

We report that the anorectic potency of neuromedin B (NMB) and gastrin-releasing peptide (GRP) is potentiated using a prefeed paradigm. During the light phase, adult male Sprague-Dawley rats (groups of n = 6) were given 30-min (pre-feed) access to a liquid diet. Thirty min later rats were injected i.p. with GRP or NMB (0, 8, 16, 32 or 64 micrograms kg-1) and given further access to the liquid diet. In prefed (PF) rats, high doses of NMB (32 and 64 micrograms kg-1) delayed the onset of eating in the test by > 10 min, significantly suppressing 30-min intake. The same doses of NMB in non prefed (NPF) rats were ineffective. Weak effects of GRP in NPF rats to reduce meal size were also enhanced under PF conditions. Exogenous GRP and NMB, in particular, appear to interact with processes stimulated by the postingestive actions of food, supporting a role for peripheral, endogenous GRP and NMB in the development of satiation and the maintenance of postprandial satiety, respectively.

Animals↗
PubMed1995

Meal pattern analysis in rats reveals partial agonist activity of the bombesin receptor antagonist BW2258U89.

The spontaneous feeding behavior of adult male rats was monitored during continuous infusion of the bombesin receptor antagonist BW2258U89 into the coeliac artery (100 micrograms kg-1 h-1) from an osmotic minipump. Nocturnal food intake was suppressed over 5 days of testing. Similar effects followed acute BW2258U89 treatment [100 micrograms kg-1, intraperitoneally (i.p.)]. Moreover, i.p. BW2258U89 mimicked the acute behavioral effects of 2 micrograms kg-1 i.p. bombesin by reducing meal size. Verifying that BW2258U89 can retain its potency throughout the entire period of chronic infusion, we demonstrated that the acute anorectic action of bombesin (4 micrograms kg-1, i.p.) was blocked by pretreatment with a BW2258U89 solution (100 micrograms ml-1 kg-1, i.p.) that was freshly prepared, or incubated for 1 or 6 days at body temperature. These data demonstrate that acute and chronic administration of BW2258U89, at a dose that abolishes the satiety effect of bombesin, significantly suppresses spontaneous feeding. Thus, BW2258U89 appears to attenuate food intake by acting as a partial agonist at peripheral receptors for bombesin-like peptides.

Amino Acid Sequence↗
PubMed1994

A novel bombesin receptor antagonist selectively blocks the satiety action of peripherally administered bombesin.

To investigate the effect of a new, specific antagonist for bombesin receptors on the satiating action of exogenous bombesin, adult male rats were adapted to a nondeprivation test regimen with daily access to a palatable liquid food. In a prefeeding paradigm, rats received intraperitoneal injections of the bombesin receptor antagonist, BW2258U89 (6.25, 25, 50, or 100 micrograms kg-1) or vehicle 20 min before, and then a second injection of either bombesin (4 micrograms kg-1), gastrin-releasing peptide (GRP; 16 micrograms kg-1), the C-terminal octapeptide of cholecystokinin (CCK-8; 4 micrograms kg-1), or vehicle 5 min before a 2-h feeding test. BW2258U89 pretreatment antagonized the satiating actions of bombesin and GRP18-27 in a very potent, dose-related manner, but did not antagonize the satiating action of CCK-8. These differential results with BW2258U89 are consistent with prior results showing the potency of this antagonist for bombesin receptor-mediated effects in visceral systems; in addition, they demonstrate the selectivity of the compound for the satiating actions of peripherally administered bombesin and bombesin-like peptides.

Animals↗
PubMed1991

Satiating effect of bombesin is mediated by receptors perfused by celiac artery.

The abdominal site or sites for the satiety action of exogenous, peripherally administered bombesin (BN) were investigated. By use of a chronic arterial catheterization technique, the effects of 1, 2, and 4 micrograms/kg BN on liquid food intake of nondeprived male rats were assessed. Comparisons were made between the effects of these doses infused into the celiac or superior mesenteric arteries or injected intraperitoneally. The satiating potency of exogenous BN was significantly enhanced by direct administration into the celiac artery, which directly perfuses the stomach, pancreas, liver, spleen, and proximal duodenum. By this route, 4 micrograms/kg BN produced greater than 60% suppression of 15-min food intake. By contrast, BN infused into the superior mesenteric artery was no more effective than intraperitoneal injection. Celiac infusion of 1 micrograms/kg BN produced a suppression (30%) of intake that was equivalent to, or exceeded, that obtained after intraperitoneal injection or superior mesenteric infusion of 4 micrograms/kg. These results strongly support an upper abdominal, and possibly gastric, site for the satiety action of peripherally administered BN.

Animals↗
PubMed1990

Enhanced anorectic potency of naloxone in rats sham feeding 30% sucrose: reversal by repeated naloxone administration.

The time-course of naloxone-anorexia was monitored in gastric-fistulated rats sham feeding sucrose (10%, 20%, 30%) solutions. Naloxone reduced sham intake dose dependently without affecting feeding initiation and in a manner which resembled the effects of progressive sucrose dilution. However, when rats sham fed 30% sucrose there was a 2-fold increase in the anorectic potency of naloxone. This exaggerated response was prevented by prior repeated naloxone treatment (5 mg/kg IP, bi-daily), concurrent with the stabilization of sham intake levels (4 days). A further experiment ruled out the possibility that tolerance develops to naloxone effects on this treatment schedule, since intact rats showed a suppression of wet mash consumption following repeated naloxone treatment which was equivalent to an acute naloxone challenge. It is proposed that 1) repeated sucrose sham feeding enhances opioid release and leads to opioid receptor adaptation (down-regulation); 2) repeated (chronic) naloxone treatments have an opposite effect on opioid receptors (up-regulation); 3) the two manipulations, in combination, counteract each other's effects. These behavioural data demonstrate dynamic changes in sham-feeding performance as a function of sucrose concentration and naloxone treatments, reinforce the importance of palatability in naloxone-anorexia, and support opioid involvement in orosensory reward.

Animals↗
PubMed1988

Bi-directional changes in sham feeding in the rat produced by benzodiazepine receptor ligands.

Both the real and sham intake of a 5% sucrose solution were increased by midazolam (3 mg/kg IP), a benzodiazepine agonist. In contrast, both the real and sham intakes of a 20% sucrose solution were reduced by Ro15-3505 (a benzodiazepine antagonist with weak inverse agonist properties) and by FG 7142 (a beta-carboline inverse agonist). These data demonstrate that drugs acting at benzodiazepine receptors can bi-directionally alter ingestional responses, probably by modulation of the oropharyngeal control of consumption.

Animals↗
PubMed1988

Naloxone attenuation of sham feeding is modified by manipulation of sucrose concentration.

The time course of sucrose (5, 10 and 20%; w/v) sham feeding was monitored in one hour tests. Intake levels increased as a function of concentration. Naloxone (1.25 mg/kg, IP) attenuated the sham feeding of 10% sucrose solution in gastric fistulated rats, without affecting initial intake rates. Furthermore, after naloxone the intake pattern of 10% sucrose was identical to that for 5% sucrose in untreated rats. In a second test, substitution of 10% sucrose by a 20% solution after 15 min of sham feeding reversed the effect of naloxone, restoring intake to 10% baseline levels. Thus naloxone's effect appeared to be behaviourally equivalent to that of sucrose dilution and was counteracted by increasing sucrose concentration. Naloxone was apparently more effective against the lower sucrose concentration, suppressing intake at an earlier stage of testing. The data confirm the importance of oropharyngeal stimulation to the suppressive action of naloxone and support opioid mediation of orosensory reward.

Animals↗
PubMed1988

Attenuation of sham feeding by naloxone is stereospecific: evidence for opioid mediation of orosensory reward.

The time course of the suppressive action of naloxone on sham feeding was examined in gastric fistulated rats. One hour sham intake of 30% sucrose solution was halved by 1.25 mg/kg IP (-)-naloxone. A maximal 75% reduction was obtained with 2.5 mg/kg. Naloxone's effect appeared to mimic the attenuation of intake rate produced by sucrose dilution. The stereoisomer (+)-naloxone (1.25, 2.5 and 10 mg/kg IP) was ineffective. These data confirm the involvement of opioid receptors in naloxone anorexia and are consistent with opioid involvement in the rewarding aspects of ingestion.

Animals↗
PubMed1987

Adrenalectomy and the anorectic effects of benzodiazepine inverse agonists and opiate antagonists in rats fed a palatable diet.

The benzodiazepine (BZ) receptor inverse agonists, FG 7142 (1.25-10.0 mg/kg, IP) and CGS 8216 (2.5-20.0 mg/kg, IP), significantly attenuated the consumption of a palatable sweetened diet by non-deprived male rats in a 30 min test. Adrenalectomy failed to affect the reduction in food intake produced by these two drugs. Similarly, the anorectic effects of the opiate antagonists, naltrexone (0.3-3.0 mg/kg, SC) and diprenorphine (0.3-3.0 mg/kg, SC) in the same feeding paradigm were unaffected by adrenalectomy. So far as palatability-induced feeding in concerned, anorectic effects of BZ inverse agonists and opiate-antagonists appear to be adrenal-independent in the rat. The benzodiazepines, clonazepam (0.3 mg/kg, IP) and diazepam (1.0 mg/kg, IP), stimulated food consumption in both adrenalectomized and sham-operated animals.

Adrenal Glands↗