H. Foo

Acute effects of kava, alone or in combination with alcohol, on subjective measures of impairment and intoxication and on cognitive performance

Kava (Piper methysticum) and alcohol were administered either separately or in combination to human subjects. Self-reports of their levels of impairment and intoxication were collected, and performance skills on a number of cognitive and visuomotor tests were determined, before and three times after consumption of the experimental drink. Kava alone had no effect on reported condition. In contrast, alcohol produced marked changes in each of the five subjective measures, all of which were in the direction of lowered ability. The combination of these two substances produced even larger negative changes on these measures. In the cognitive tests, kava produced a decrement in performance on Digit Symbol Coding. Alcohol produced a significant decrease in performance on a divided attention test, which was almost entirely on the peripheral, discontinuous component of the test. The combination of kava and alcohol produced an even greater decrease in performance on this test, and in the same component. The present findings suggest that kava alone has little effect on reported condition and cognitive performance, but appears to potentiate both perceived and measured impairment when combined with alcohol.

Analgesia Accompanying Food Consumption Requires Ingestion of Hedonic Foods

Animals eat rather than react to moderate pain. Here, we examined the behavioral, hedonic, and neural requirements for ingestion analgesia in ad libitum fed rats. Noxious heat-evoked withdrawals were similarly suppressed during self-initiated chocolate eating and ingestion of intraorally infused water, sucrose, or saccharin, demonstrating that ingestion analgesia does not require feeding motivation, self-initiated food procurement, sucrose, or calories. Rather, food hedonics is important because neither salt ingestion nor quinine rejection elicited analgesia. During quinine-induced nausea and lipopolysaccharide (LPS)-induced illness, conditions when chocolate eating was presumably less pleasurable, analgesia accompanying chocolate consumption was attenuated, yet analgesia during water ingestion was preserved in LPS-injected rats who showed enhanced palatability for water within this context. The dependence of ingestion analgesia on the positive hedonics of an ingestate was confirmed in rats with a conditioned taste aversion to sucrose: after paired exposure to sucrose and LPS, rats no longer showed analgesia during sucrose ingestion but continued to show analgesia during chocolate consumption. Eating pauses tended to occur less often and for shorter durations in the presence of ingestion analgesia than in its absence. Therefore, we propose that ingestion analgesia functions to defend eating from ending. Muscimol inactivation of the medullary raphe magnus blocked the analgesia normally observed during water ingestion, showing the involvement of brainstem endogenous pain inhibitory mechanisms in ingestion analgesia. Brainstem-mediated defense of the consumption of palatable foods may explain, at least in part, why overeating tasty foods is so irresistible even in the face of opposing cognitive and motivational forces.

Hypoalgesia elicited by a conditioned stimulus is blocked by a μ, but not a δ or a κ, opioid antagonist injected into the rostral ventromedial medulla

The present study investigated the role of micro, delta, and kappa receptors within the RVM in mediating expression of conditional hypoalgesia (CHA). Five groups of rats with RVM cannulae were given daily sessions of paired or unpaired presentations of an auditory CS (white noise) and foot shock across three consecutive days. On the test day, rats in the Paired condition were injected with the micro antagonist CTAP, the delta antagonist naltrindole, the kappa antagonist nor-BNI, or saline. Rats in the Unpaired condition were injected with saline. TFLs were measured before and after injections, as well as during and after presentations of the CS. The results showed that none of the drugs affected baseline TFLs. During CS presentation, rats in the Paired condition injected with saline showed longer TFLs than those in the Unpaired condition given saline, confirming the presence of CHA. Expression of this response was blocked by CTAP, but was unaffected by naltrindole or nor-BNI. These results suggest that mu, but not delta or kappa, opioid receptors in the RVM mediate expression of CHA.

Naloxone-induced hypoalgesia: Effects of noradrenergic antagonists and agonist

The present experiments confirmed that rats injected with naloxone and exposed to a heated floor acquired a hypoalgesic response, as indexed by the latencies to lick their paws. The expression of these latencies were unaffected by yohimbine, clonidine, propranolol, or by relatively moderate doses of prazosin, suggesting that the conditioned hypoalgesic response induced by pairings of naloxone and a heated floor is not mediated by the release and turnover of noradrenaline.

Expression of antinociception in response to a signal for shock is blocked after selective downregulation of μ-opioid receptors in the rostral ventromedial medulla

Prior work has shown that release of endogenous ligands for mu-opioid receptors in the rostral ventromedial medulla (RVM) is critical for the modulation of spinal nociceptive reflexes observed during stress. In the present study, we used antisense oligodeoxynucleotides (AS ODN) to suppress synthesis of mu-opioid receptors in the RVM prior to activating descending antinociceptive systems with a signal for foot shock. Five groups of rats with RVM cannulae were trained with paired or unpaired exposures to white noise (WN) and foot shock. Over several days, they received RVM infusions of an AS ODN probe targeting exon 1 of the cloned MOR-1 receptor, an inactive missense (MS) ODN with the same base composition in which the sequence for four bases was changed, an AS ODN probe targeting exon 4, or saline. Tail-flick latencies (TFLs) were measured before, during, and after presentation of the auditory signal for shock. Rats given paired training and saline injections displayed longer TFLs than saline control rats given unpaired exposures to WN and shock, confirming the ability of the conditional stimuli (CS) to elicit antinociception. Expression of this conditional hypoalgesia (CHA) was attenuated by pretreatment with the AS ODN probe targeting exon 1, but was unaffected by pretreatment with AS ODN probe targeting exon 4 or MS ODN sequence for exon 1. However, pretreatment with the AS ODN probe targeting exon 1 did not affect expression of conditional freezing to other shock-associated cues. Testing of the same animals several days after the ODN injections showed that the attenuating effect on expression of CHA were reversible. These results support the idea that mu-opioid receptors in the RVM are critically involved in mediating expression of hypoalgesia following stress. They also provide further evidence for dissociation in the mechanisms mediating expression of aversive conditional responses.

Activation of kappa opioid receptors in the rostral ventromedial medulla blocks stress-induced antinociception.

Prior work has shown that kappa opioids may attenuate the effects of analgesic μ receptor agonists in some neural circuits related to pain modulation. This study examined whether hypoalgesia following exposure to a signal for shock is attenuated by infusions of the κ agonist U69593 into the rostral ventromedial medulla (RVM). Rats were trained with paired or unpaired presentations of white noise and foot shock. On test days, tail flick latencies were measured before, during, and after exposure to the auditory conditioned stimulus (CS). One of three doses of U69593 (0.0445, 0.178 and 1.00 μg) or an equivalent volume of saline was injected into the RVM. Rats that had received noise-shock pairings displayed conditional hypoalgesia (CHA) compared to those given unpaired presentations. Expression of CHA was completely blocked by the highest dose of U69593 (1.00 μg) injected 20 min before testing, indicating an antagonistic effect of U69593 on expression of CHA. These findings are discussed in terms of the evidence for antagonism of morphine- and DAMGO-induced hypoalgesia by κ agonists.

Naloxone-induced hypoalgesia: Evidence from the formalin test

Two experiments examined the hypoalgesic effects that accrue from pairing exposure to a heat stressor with the opioid antagonist naloxone. Experiment 1 confirmed that rats given separate exposures to a heated floor and to naloxone are hypoalgesic when then tested on that floor. Further, the results confirmed that pairing the initial exposure to the heat stressor with naloxone resulted in a more profound hypoalgesic response. Experiment 2 provided new evidence for the hypoalgesic effects of separate exposures to the heat stressor and to naloxone, and for naloxones enhancement of acquisition of the hypoalgesia, in rats tested for responsiveness to formalin. These results, therefore, demonstrate generalisability of the hypoalgesic effects across assays for acute and chronic pain.

Eating is a protected behavior even in the face of persistent pain in male rats

Feeding is critical for survival. Yet, patients with chronic pain often lose their appetite and eat less. We previously showed that ad libitum fed male rats continue to feed rather than withdraw from a brief noxious stimulus. This study examined the effects of a sustained noxious stimulus on feeding by testing ad libitum fed male rats for five eating behaviors--latency to eat, time taken to eat each chip, pauses and scanning during eating, and the number of chocolate chips eaten--during the hour following a sham injection or an injection of a low (0.5%) or moderate (1.5%) dose of formalin into the hind paw. Sham-injected rats showed no pain-related behaviors, rats injected with 0.5% formalin showed very few pain-related behaviors, and rats injected with 1.5% formalin showed favoring, lifting and licking of the injured paw with a characteristic biphasic time course. Besides taking less time to commence eating during the first phase of formalin pain, rats injected with either dose of formalin did not differ from sham-injected rats on any of the other eating measures. Rats injected with 0.5% formalin showed no pain behaviors during eating, whereas those given 1.5% formalin typically ate while not exhibiting any pain behaviors but occasionally ate while favoring the paw, rarely while lifting the paw, and never while licking the paw. These results show that eating is a protected activity even in the presence of persistent pain in male rats.

Food Consumption Inhibits Pain‐related Behaviors

The function of the endogenous analgesia system under natural circumstances has been little explored. Our recent work shows that animals are significantly less responsive to noxious stimulation during slow wave sleep, micturition, and while eating than during quiet wake. The analgesia associated with eating is dependent on activity in the medullary raphe magnus, the final common brain stem region in endogenous analgesia pathways. Eating analgesia does not depend on energy‐depletion due to food deprivation. Further, analgesia accompanies chow‐eating even though chow has no sucrose, demonstrating that sucrose is not a necessary component of analgesia‐evoking ingestates. Since raphe magnus modulates processing of innocuous as well as nociceptive information, the sensory suppression accompanying eating is likely a more general depression of the response to external stimulation. Such a phenomenon would serve animals well under natural conditions where energy‐dense food is scarce but has counterproductive effects, possibly contributing to obesity, in modern human society where energy‐dense food is readily available.

The form of the conditioned hypoalgesic response resulting from preexposure to a heat Stressor depends on the pain test used

Preexposure to the heated floor of a hot-plate apparatus resulted in conditioned hypoalgesic responses among rats tested in that apparatus. These responses were unaffected by naloxone or a history of morphine among rats tested on the heated floor, but were reversed by naloxone or a history of morphine in rats tested with formalin on the nonheated floor of the apparatus. The results were taken to mean that apparatus cues paired with the heated floor conditionally activated multiple mechanisms of pain control; the nonopioid mechanisms were engaged by the pain that was provoked by the test exposure to the heated floor and the opioid mechanisms were recruited by the pain that was produced by formalin.