Tonic nociception in neonatal rats McLaughlin, C R; Lichtman, A H; Fanselow, M S ...
Pharmacology, biochemistry and behavior,
08/1990, Volume:
36, Issue:
4
Journal Article
Peer reviewed
The issues of whether infants detect noxious stimuli and whether their nociceptive responses are suppressed by analgesics has been the focus of considerable controversy. Therefore, to more completely ...assess the nociceptive responses of neonatal rat pups to tonic pain, we tested 3-day-old rat pups using the formalin test. The responses of the young pups to formalin-produced injury were similar to those observed in adult rats, both behaviorally and in terms of their responsivity to morphine-induced antinociception. These results provide the first clear-cut evidence of integrated tonic pain responses in the neonate.
Methamphetamine is a popular drug of abuse, readily synthesized in clandestine laboratories. Illicitly obtained methamphetamine is frequently impure, containing various purposefully added diluents ...and adulterants, as well as impurities of manufacture and origin. Few impurities have been studied in vivo and limited information exists concerning their pharmacology/toxicology. One such impurity of manufacture is α-benzyl-
N-methylphenethylamine (BNMPA). Acute toxicity and spontaneous activity (locomotor) studies were conducted with this compound alone and in combination with S(+)-methamphetamine (METH) in male, ICR mice. In the acute toxicity studies, BNMPA was evaluated for convulsant activity. While BNMPA also produced some behavioral disturbances similar to those seen with methamphetamine (e.g., stereotopy) at doses greater than 30 mg/kg, no tonic-clonic convulsions were noted until pre-terminal convulsions at 50 mg/kg. METH alone produced tonic-clonic convulsions at terminal doses of 70 mg/kg. When BNMPA was given in combination with METH, there was no readily apparent change in the convulsion profile from that of METH given alone. In spontaneous activity studies, doses of BNMPA ranging from 1 mg/kg to 50 mg/kg failed to alter locomotor activity significantly from controls though 5 mg/kg METH alone significantly increased spontaneous activity. In addition, increases in spontaneous activity elicited by 5 mg/kg METH were not affected when METH was given with 5 mg/kg BNMPA. While BNMPA appears to have toxic effects in the central nervous system (CNS), the failure to affect locomotor activity or alter either METH-induced increases in spontaneous activity or METH-induced convulsions suggests that the two agents are producing their effects through distinct mechanisms.
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The cardiovascular effects elicited by volatilized cocaine were compared to those produced by i.v. drug administration. All of the subjects exposed to volatilized cocaine exhibited an initial ...increase in mean arterial pressure (MAP), profound bradycardia, and heart blocks. Intravenous administration of cocaine (1.5 mg/kg i.v.), a dose equivalent to the amount of drug subjects received from inhalation exposure, led to a transient increase in MAP but failed to produce any obvious ECG abnormalities or bradycardia; however, increasing the dose to 4.5 mg/kg resulted in considerable toxicity. Finally, the hemodynamic effects elicited by inhalation cocaine were found to undergo rapid tolerance during the first 5-min exposure period and the three subsequent drug exposures.
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Experiments examined the effect of Pro-Leu-Gly-NH2 (MIF) on the acquisition of tolerance to morphine-induced antinociception and its efficacy as a cue predictive of morphine administration. Test ...results are discussed.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
It has been proposed that cannabinoids act at a Gi protein-coupled receptor to produce antinociception. One action of Gi-proteins is to decrease intracellular cAMP via inhibition of adenylyl cyclase ...activity. Although cannabinoid inhibition of forskolin-stimulated adenylyl cyclase is used as a confirmation of functional cannabinoid receptors, it is unknown whether this second messenger system specifically mediates cannabinoid-induced antinociception. This
in vivo study was conducted using enantiomeric cAMP analogs, Rp-cAMPS (an antagonist) and Sp-cAMPS (an agonist), and the cAMP agonist Cl-cAMP to test the hypothesis that cannabinoid-induced antinociception is due to decreased adenylyl cyclase activity. None of the cAMP analogs, forskolin, or 1,9-dideoxy-forskolin affected Δ
9-THC or CP-55,940-induced antinociception produced by intrathecal (i.t.) or intracerebroventricular (i.c.v.) injections in mice. Experiments were also conducted to investigate whether i.c.v. administration of Sp-cAMPS would block i.c.v. cannabinoid-induced antinociception in rats. Sp-cAMPS failed to block CP-55, 940-induced antinociception. However, Sp-cAMPS produced hyper-excitability and reactive behavior indicating that it did elicit a pharmacological effect. Although, adenylyl cyclase may mediate other cannabinoid-induced actions, these results do not support the hypothesis that it is involved in cannabinoid-induced antinociception. Alternatively, other effector systems such as calcium or potassium channels coupled to cannabinoid receptors may mediate cannabinoid-induced antinociception.
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delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the ...structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects.
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The present study describes a wheel turn/tail flick paradigm that was designed to simultaneously assess nociceptive thresholds of responses organized at spinal and supraspinal levels of the CNS in ...the rat. The paradigm involves training rats to perform an operant wheel turn response in order to escape current applied to the tail. Thresholds for the supraspinally organized escape response and the spinally organized tail flick reflex were determined via the psychophysical method of constant stimuli. Response latencies for wheel turn escape and tail flick were recorded to determine whether changes in nociceptive thresholds were confounded with changes in motor performance. The systemic administration of 3 mg/kg morphine sulfate elevated thresholds for both responses, but escape thresholds were elevated to a greater degree than tail flick thresholds. Because response latencies at threshold were not affected by morphine treatment, it appears that performance deficits did not contribute to the increase in thresholds. Advantage of these psychophysical procedures in assessing nociceptive responding in animals are discussed.
In the past decade a tremendous amount of research has demonstrated that stressful stimuli can activate endogenous antinociceptive mechanisms. A common strategy in studying the neural mechanisms that ...subserve stress-induced antinociception (SIA) is to examine whether it is attenuated by naloxone or naltrexone. SIA can also be produced by the presentation of a previously neutral stimulus that has been paired with electric shock through a Pavlovian fear conditioning procedure. Despite several reports indicating that conditional analgesia was not blocked by naloxone or naltrexone, a prevalent view in the literature assumes that conditional analgesia should always be blocked by opiate antagonists. Therefore, the present series of studies examined several variables that might determine whether conditional analgesia is naltrexone reversible. Experiment 1a and 1b examined whether the shock intensity during training would determine naltrexone-reversibility in the tail flick and formalin tests, respectively. In both tests conditional analgesia was unaffected by naltrexone. Experiment 2 and 3 varied the amount of training during training in the tail flick and formalin tests. In the tail flick test the efficacy of naltrexone in attenuating conditional analgesia was inversely related to the amount of training that the subjects had received during acquisition. However, in the formalin test conditional analgesia was unaffected by naltrexone pretreatment. Experiment 4 demonstrated that nonreinforced exposure to the CS extinguishes conditional increases in tail flick latency. Experiments 5 and 6 examined the neurochemical mechanisms underlying conditional analgesia at the spinal level. Both forms of conditional analgesia were completely prevented by intrathecal administration of the noradrenergic antagonist yohimbine. In contrast, neither quaternary naltrexone nor the serotonin antagonist, methysergide, consistently blocked conditional analgesia. These results indicate that at the spinal level both forms of conditional analgesia are subserved by critical alpha-noradrenergic synapses.
These studies investigated the role that social facilitation, availability of the dam, and milk play in the maintenance of suckling behavior. Beginning at Day 20, rat pups' suckling experiences were ...restricted to testing with an anesthetized dam. In the first experiment, nipple attachment was abandoned by about Day 25 in rats that were tested alone with an anesthetized dam for 1 hr per day. When tested in groups of four, nipple attachment was maintained until about Day 27. Increasing exposure to an anesthetized dam to 2 hr per day prolonged nipple attachment about another 4 days. In the second experiment, pups were given either one or two daily 1-hr attachment tests and tested with either an anesthetized dam or an anesthetized dam in which the milk letdown reflex was reinstated. Both increasing the daily exposure to an anesthetized dam and reinstating milk letdown significantly prolonged suckling. Pups given two daily exposures to an anesthetized, milk-laden dam attached until about Day 47, long past the normal age of weaning.
