Biomedical subjects

M S Fanselow

Publications and source records attributed to M S Fanselow.

At least 55 records · Page 3Linked to original sources

PubMed1993

The development of morphine-induced antinociception in neonatal rats: a comparison of forepaw, hindpaw, and tail retraction from a thermal stimulus.

Two parallel experiments in rats 2-21 days of age investigated the onset and characteristics of morphine-induced antinociception. One measure of reactivity to pain, limb retraction from a hotplate, was utilized for three different limbs (forepaw, hindpaw, and tail) to chart the development of opioid sensitivity. Morphine-induced antinociception, even in 2-day-old rats, was obtained for all limbs, in a dose-related fashion, and reached peak sensitivity at 6-7 days of age. Naltrexone did not affect limb retraction latencies in nonmorphine treated rats at any age. These studies demonstrate early antinociception to low doses of an opiate and establish that the pain system, like positive reinforcement systems, is opiate sensitive.

Analgesics↗

PubMed1993

Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear.

The effects of amygdala, hippocampus, and periaqueductal gray (PAG) lesions on contextual fear conditioning in rats were examined. Freezing behavior served as the measure of conditioning. Unlesioned control animals showed reliable conditional freezing in the testing chamber when observed both immediately and 24 hr after footshocks. In contrast, rats with amygdala or ventral PAG lesions exhibited a significant attenuation in freezing both immediately and 24 hr after the shocks. Dorsal PAG lesions had no effect on freezing at either time. Animals with hippocampal lesions displayed robust freezing behavior immediately following the shock, even though they showed a marked deficit in freezing 24 hr after the shock. These results indicate that there are anatomically dissociable short- and long-term conditional fear states.

Amygdala↗

PubMed1993

Mechanisms responsible for reduced contextual conditioning with massed unsignaled unconditional stimuli.

Massed presentation of unsignaled shock results in less conditional freezing to contextual cues than do distributed presentations. Consistent with an account of the learning deficit based on the perceptual-defensive-recuperative theory, the massed-shock deficit was attenuated by preexposure to shock or the conditioning context. This formulation was also successfully applied to the deficit in conditioning that occurs when a single shock is given immediately after placement in a context. Opponent-process theory was not supported by 2 findings: (a) The deficit was neither enhanced by shock preexposure nor reduced by an opioid antagonist, and (b) unconditional reactions were greater with massed shock. Inconsistent with the suggestion that the effect is a performance artifact specific to freezing, the massed-shock deficit was apparent for a 2nd measure of conditioning.

Animals↗

PubMed1992

Modality-specific retrograde amnesia of fear.

Emotional responses such as fear are rapidly acquired through classical conditioning. This report examines the neural substrate underlying memory of acquired fear. Rats were classically conditioned to fear both tone and context through the use of aversive foot shocks. Lesions were made in the hippocampus either 1, 7, 14, or 28 days after training. Contextual fear was abolished in the rats that received lesions 1 day after fear conditioning. However, rats for which the interval between learning and hippocampal lesions was longer retained significant contextual fear memory. In the same animals, lesions did not affect fear response to the tone at any time. These results indicate that fear memory is not a single process and that the hippocampus may have a time-limited role in associative fear memories evoked by polymodal (contextual) but not unimodal (tone) sensory stimuli.

Amnesia, Retrograde↗

PubMed1992

Associative regulation of Pavlovian fear conditioning: unconditional stimulus intensity, incentive shifts, and latent inhibition.

Conditional stimuli (CS) associated with painful unconditional stimuli (US) produce a naloxone-reversible analgesia. The analgesia serves as a negative-feedback regulation of fear conditioning that can account for the impact of US intensity and CS predictiveness on Pavlovian fear conditioning. In Experiment 1 training under naloxone produced learning curves that approached the same high asymptote despite US intensity. Shifting drug treatment during acquisition had effects that paralleled US intensity shifts. In Experiment 3 naloxone reversed Hall-Pearce (1979) negative transfer using a contextual CS, indicating that conditional analgesia acquired during the CS-weak-footshock phase retards acquisition in the CS-strong-footshock phase. Experiment 5 used a tone CS in both a latent-inhibition and a negative-transfer procedure. Only negative transfer was blocked by naloxone. Therefore, negative transfer but not latent inhibition is mediated by a reduction of US processing.

Animals↗

PubMed1992

The benzodiazepine inverse agonist DMCM as an unconditional stimulus for fear-induced analgesia: implications for the role of GABAA receptors in fear-related behavior.

When the benzodiazepine inverse agonist DMCM (6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methyl ester) occupies the benzodiazepine recognition site on the GABAA receptor complex, the inhibitory action of gamma-aminobutyric acid (GABA) is attenuated. DMCM acted as an unconditional stimulus for one response associated with fear or anxiety, analgesia, as indicated by a dose-dependent (0.25-1.0 mg/kg) suppression of rats' responses to a formalin injection. This was accompanied by other fearlike responses (defecation and urination). The opioid antagonist naltrexone (1.75-14 mg/kg) did not affect these behaviors. Environmental cues associated with DMCM provoked analgesia and defecation in the absence of the drug. The conditional analgesia was reversed by naltrexone (7 mg/kg). DMCM functions as an unconditional fear stimulus by eliciting fear-related behaviors and conditioning those responses to neutral stimuli. The neural circuitry underlying fear conditioning appears to involve tonically inhibitory GABAergic synapses.

Animals↗

PubMed1992

Selective impairment of long-term but not short-term conditional fear by the N-methyl-D-aspartate antagonist APV.

Previous research has indicated that the competitive N-methyl-D-aspartate (NMDA) antagonist APV (DL-2-amino-5-phosphonovalerate) prevents the Pavlovian conditioning of fear to contextual stimuli when tested 24 hr, but not immediately, after training. The present study investigated this differential time-dependent effect of APV on fear conditioning. Rats were given either APV or saline and presented with 3 footshocks in a distinctive chamber. Promptly after the shock, rats that had received APV exhibited a species-typical fear response-freezing. However, the freezing lasted for only a short period of time (less than 3 min) compared with that of controls. An immediate-shock procedure showed that freezing was entirely a conditional response to the chamber. In addition, the results of a savings test suggest that APV impairs storage rather than retrieval processes. These results indicate that there are two temporally distinct associative fear processes, a short-term NMDA-independent conditional fear and a long-term NMDA-dependent conditional fear.

2-Amino-5-phosphonovalerate↗

PubMed1991

N-methyl-D-aspartate receptor antagonist APV blocks acquisition but not expression of fear conditioning.

The role of N-methyl-D-aspartate (NMDA) receptors in Pavlovian fear conditioning was examined using the NMDA antagonist DL-2-amino-5-phosphonovaleric acid (APV). Either APV (5 micrograms/rat) or saline was administered before the training phase, the testing phase, or both. APV completely blocked acquisition but not expression of fear conditioning. The L enantiomer of APV did not affect the acquisition of conditional fear. To separate encoding from consolidation processes, APV was administered either before or immediately after the footshock unconditional stimulus (US) during the training phase. The results indicate that APV must be present during the US to produce its effects on fear conditioning. The behavioral effect of the drug is not due to analgesic action because APV did not alter pain sensitivity. The data suggest that NMDA receptors are critical for the acquisition but not expression of fear conditioning. These effects on fear conditioning are parallel to the in vitro effects of APV on the acquisition but not expression of long-term potentiation (LTP) and suggest that endogenously generated NMDA-dependent LTP participates in the neural plasticity underlying fear conditioning.

2-Amino-5-phosphonovalerate↗

PubMed1991

Opioid and nonopioid conditional analgesia: the role of spinal opioid, noradrenergic, and serotonergic systems.

The first aim of this study was to test whether opioid mediation of conditional analgesia is inversely related to the relative amount of training that rats received, a prediction derived from the severity hypothesis. Naltrexone attenuated the analgesia among subjects in the low-training group but had no effect in rats given an extended amount of training. The second aim of this study was to investigate whether noradrenergic, opiate, and serotonergic spinal systems play a role in conditional analgesia. Intrathecal administration of yohimbine, an alpha 2 antagonist, completely blocked both opioid and nonopioid forms of conditional analgesia. Spinal administration of either quaternary naltrexone or methysergide failed to have an effect. In addition to providing support for the severity hypothesis, these results indicate that both opioid and nonopioid forms of conditional analgesia are subserved by critical alpha 2-adrenoceptors at the spinal level.

Animals↗

PubMed1990

Cats produce analgesia in rats on the tail-flick test: naltrexone sensitivity is determined by the nociceptive test stimulus.

Previous research has demonstrated that exposure to a cat produces a naltrexone-reversible antinociception as assessed in the formalin test in rats. Because different neurochemical mechanisms inhibit different forms of nociception, the present study examined whether presentation of a cat would also produce a naltrexone-reversible antinociception in the tail-flick response to radiant heat and electric shock. Exposure to the cat produced antinociception in both tail-flick paradigms. Naltrexone blocked the inhibition of the thermally evoked tail-flick response, but had no effect in the electric shock tail-flick paradigm. These results indicate that opioid mediation of stress-induced analgesia is determined, in part, by the nociceptive test employed.

Animals↗

PubMed1990

Tonic nociception in neonatal rats.

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.

Animals↗

PubMed1990

Centrally administered opioid antagonists, nor-binaltorphimine, 16-methyl cyprenorphine and MR2266, suppress intake of a sweet solution.

Three opioid antagonists (MR2266, 16-methyl cyprenorphine and nor-binaltorphimine) were tested independently for their ability to suppress the intake of a highly palatable saccharin and glucose (S/G) solution after central administration. MR2266 is an equally potent antagonist at kappa (kappa) and mu (mu) opioid receptors. Nor-binaltorphimine (N-BNI) and 16-methyl cyprenorphine (M80) are two recently developed opioid antagonists that were chosen based upon their ability to act more selectively than naloxone at kappa and delta (delta) opioid receptor types, respectively. Prior research has demonstrated that when dissolved in acid and administered centrally, MR2266 (20 micrograms) fails to suppress S/G intake. Because all three antagonists are rather insoluble in water, they were dissolved in dimethyl sulfoxide (DMSO). Rats with chronic ventricular cannula were allowed to consume S/G for a 0.5 hr bout. They received a single intracerebroventricular (ICV) injection of antagonist (MR2266: 0, 10, 20 and 40 micrograms; M80: 0, 5, 10, 20 and 40 micrograms or N-BNI: 0, 1, 3, and 10 micrograms) 10 min prior to the start of the drinking bout. Administration of DMSO alone failed to alter drinking relative to saline, whereas each antagonist significantly attenuated S/G intake. We conclude that, when dissolved in DMSO, these antagonists suppress drinking by blockade of opioid receptors.

Animals↗

PubMed1989

Delta opioid antagonist, 16-Me cyprenorphine, selectively attenuates conditional fear- and DPDPE-induced analgesia on the formalin test.

The effects of 16-Me cyprenorphine (M80) on the antinociception produced by reexposing rats to a chamber associated with footshock (1 mA, 0.75 sec) 24 hr earlier was assessed with the formalin test. In Experiment 1, intracerebroventricular administration of M80 dose-dependently (0.5-8 micrograms) reversed conditional analgesia. Experiment 2 demonstrated that M80 (5 micrograms) had no effect on baseline pain sensitivity, but completely reversed conditional analgesia. Experiment 3 demonstrated that 0.25 micrograms DAGO, 3.5 micrograms DPDPE, and 28 micrograms U50,488H all produced equivalent levels of antinociception on the formalin test. The 5 micrograms dose of M80 completely reversed the antinociception produced by DPDPE but did not influence that produced by DAGO or U50,488H. These data suggest, that at the doses employed, M80 is a selective delta-opioid receptor antagonist and that delta-receptors are involved in conditional fear-induced analgesia.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1989

Suppression of juvenile social behavior requires antagonism of central opioid systems.

Pairs of male and female rats were injected with either tertiary naltrexone (NTX) which readily crosses the blood-brain barrier, or quaternary naltrexone (QNTX) which does not, to determine the importance of central opioid systems in the elaboration of juvenile social behavior. In the first experiment, only intraperitoneal injections of NTX (1.0 mg/kg) suppressed the frequency of wrestling pins. Peripheral injections of QNTX (10.0 mg/kg) were without effect. In a second experiment, QNTX (2.0, 4.0, or 8.0 micrograms/4.0 microliters) was injected directly into the lateral ventricles. Intracerebroventricular injection of the moderate dose reliably reduced frequency of pinning while the higher dose was severely incapacitating and the low dose was without effect. The results of these two experiments confirm an important role for brain opioid systems in the control of juvenile social interaction.

Animals↗

PubMed1989

Pro-Leu-Gly-NH2 serves as a conditioned stimulus in the acquisition of conditioned tolerance.

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 was examined. Daily administration of MIF prior to morphine injection did not attenuate the acquisition of tolerance to the antinociceptive properties of morphine, as measured by the latency to hindpaw lick in a hot-plate test of analgesia. When the animals were tested 72 hr later without MIF pretreatment, they appeared to lose tolerance, as indicated by longer latencies to paw lick. These data suggest that in some situations MIF may interfere with the acquisition of tolerance by acting as a cue that reliably predicts the antinociceptive properties of morphine.

Animals↗

PubMed1989

Modulation of appetitively and aversively motivated behavior by the kappa opioid antagonist MR2266.

MR2266 (MR), an opioid antagonist that binds to kappa and mu receptors, was examined for its ability to influence the aversively motivated behaviors conditioned by electric shock and the drinking induced by water deprivation or the availability of a palatable saccharin/glucose solution. The intraperitoneal (ip) and intracerebroventricular (icv) administration routes were contrasted. After both ip and icv administration, MR was able to reverse conditional analgesia as measured by the formalin test. MR enhanced the Pavlovian conditional freezing response when administered icv prior to shock exposure but reduced freezing if given ip prior to shock. A related benzomorphan-derived opioid antagonist, MR1452, also reduced freezing when given ip prior to shock. MR2266 was a potent antidipsogenic agent when administered ip but had no such effect when administered icv. It is concluded that separable opioid systems are involved in the modulation of appetitively and aversively motivated behaviors.

Animals↗

PubMed1989

Role of mu and kappa opioid receptors in conditional fear-induced analgesia: the antagonistic actions of nor-binaltorphimine and the cyclic somatostatin octapeptide, Cys2Tyr3Orn5Pen7-amide.

When rats are returned to an environment in which they previously received electric shock they show a reduction in sensitivity to painful stimuli. This conditional fear-induced analgesia was measured using the formalin test. The octapeptide Cys2Tyr3Orn5Pen7-amide (CTOP; 0, 10, 40 and 160 ng/rat) dose-dependently reversed conditional analgesia when administered i.c.v. The 40-ng dose partially attenuated fear-induced analgesia, whereas the 160-ng dose reversed it completely. Using similar procedures, CTOP was tested for its ability to reverse the analgesia produced by i.c.v. administered [D-Ala2,-NMPhe4, Glyol5]-enkephalin, [D-Pen2,D-Pen5]-enkephalin and U50488H, which are highly selective opioid agonists at mu, delta and kappa receptors, respectively. At 40 ng/rat, CTOP reversed the analgesia produced by the mu selective ligand but not that produced by the delta ligand or the kappa ligand. At 80 ng CTOP antagonized the analgesia produced both by both enkephalin analogs but not U50488H. Nor-binaltorphimine (0, 1, 3, 10 and 30 micrograms/rat) had no effect on conditional analgesia. However, the 10- and 30-micrograms doses could reverse completely the analgesia produced by U50488H. Therefore, it appears that mu and delta, but not kappa receptors, are involved in this opioid form of stress-induced analgesia.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1988

Analgesia produced by centrally administered DAGO, DPDPE and U50488H in the formalin test.

Three opioid agonists ([D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAGO), [D-Pen2,D-Pen5]enkephalin (DPDPE) and U50488H) were tested independently for their ability to produce analgesia in the formalin test. These agonists were chosen based upon their ability to act selectively at mu, delta and kappa opioid receptor types respectively. Rats received one intracerebroventricular (i.c.v.) injection of an agonist 20 min after subcutaneous injection of 15% formalin into a rear paw. Formalin injection produces continuous pain that results in two stereotypic behaviors, paw licking and paw lifting. Ten minutes after i.c.v. injection rats were observed for an 8 min period and scored for formalin-induced behavior. All agonists produced analgesia as indicated by a dose-dependent attenuation of formalin-induced behavior. At the doses tested, the rank order of analgesic efficacy was DAGO greater than DPDPE greater than U50488H. We suggest that centrally located mu, delta and kappa opioid receptors can each modulate the perception of this clinically relevant form of continuous pain. Additionally, the highest dose of DPDPE tested significantly increased rearing whereas DAGO and U50488H failed to affect rearing.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗