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Biomedical subjects

D J Mayer

Publications and source records attributed to D J Mayer.

At least 55 records · Page 3Linked to original sources
PubMed1990

Differential uptake of HRP by intact axon terminals versus transected axons: a study on bulbospinal fibers in the dorsolateral funiculus.

A comparison was made of the amount of HRP uptake from transected versus intact axonal endings of rostral ventromedial medulla (RVMM) and locus coeruleus cells projecting via the dorsolateral funiculus in the rat. We found that retrograde labelling in the RVMM was reliably different between treatments, while locus coeruleus retrograde labelling was highly variable and not reliably different. HRP applied to intact endings retrogradely labelled approximately twice as many RVMM cells, including 25 times as many 5-hydroxytryptamine (B3) cells, as HRP applied to transected axons. In this first quantitative assessment of HRP uptake from transected versus intact endings, reliable differences have been found. These results have implications for the neural circuitry involved in pain modulatory systems.

Animals↗
PubMed1990

Chronic administration of cholecystokinin antagonists reverses the enhancement of spinal morphine analgesia induced by acute pretreatment.

The effects of acute and chronic (22 days) treatment with the cholecystokinin (CCK) antagonists proglumide and lorglumide on antinociception induced by intrathecal (i.t.) morphine were determined at weekly intervals with the rat tail-flick assay. On day 1, acute pretreatment with either proglumide (20 ng, i.t.) or lorglumide (7 ng, i.t.) enhanced morphine (1 microgram, i.t.) analgesia compared to saline (1 microliter, i.t.) pretreatment, but this facilitation was absent on days 8 and 15 of CCK antagonist treatment and was replaced by attenuation of opioid antinociception on day 22. Following termination of daily proglumide or lorglumide injections, normal (control) morphine response was observed after pretreatment with either CCK antagonist on days 29 and 36. Weekly co-administration of either drug with morphine had similar effects: opioid antinociception was initially enhanced on day 1, but this amplification was lost by day 8 and remained absent for the duration of the study (i.e., up to day 36). Inhibition of morphine analgesia, however, was not observed with this treatment paradigm. Chronic daily administration of either CCK antagonist alone did not lower nociceptive thresholds; further, normal opioid response was retained throughout the study in saline treated controls receiving morphine weekly. This study demonstrates that whereas acute i.t. administration of CCK antagonists enhances i.t. morphine antinociception, chronic treatment causes loss of facilitation or attenuation of opioid antinociception, suggesting that (1) compensatory alterations in CCK-opioid interactions develop during chronic CCK blockade and (2) CCK antagonists may not be useful adjuncts to opioid analgesics in the management of chronic pain in man.

Analgesia↗
PubMed1990

Opioid inhibition of kainic acid-induced scratching: mediation by mu and sigma but not delta and kappa receptors.

Scratching induced by intrathecal (IT) administration of kainic acid (0.5 nmol) to rats was inhibited by IT pretreatment with the selective mu agonists levorphanol (30 and 90 nmol), [D-Ala2,N-Met-Phe4,Gly5-ol]-enkephalin (DAGO, 0.4 and 1.1 nmol), or morphine (90 nmol), the mixed mu-delta agonist [D-Ala2,D-Leu5]-enkephalinamide (DADLE, 10 and 30 nmol), or the sigma/phenycyclidine (PCP) agonists dextrorphan (90 nmol) or (+)-N-allyl-N-normetazocine ([+]-NAM, 90 nmol). The kappa agonists dynorphin (1.1 nmol) and ethylketocyclazocine (EKC, 90 nmol) had no significant effect, nor did the selective delta agonist [D-Pen2,D-Pen5]-enkephalinamide (DPDPE, 90 nmol). The nonopioids (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([+]-3-PPP, 90 nmol) and PCP (90 nmol), selective for sigma and PCP sites, respectively, both antagonized kainic-induced scratching. Levorphanol- and DADLE-induced attenuation of scratching was partially antagonized by naltrexone. These findings suggest that opioid inhibition of kainic acid-induced scratching is mediated by classical mu receptors as well as sigma and PCP sites.

Animals↗
PubMed1990

Spinal paralysis and catalepsy induced by intrathecal injection of opioid agonists.

The intrathecal administration of high (1.05 mumol) doses of D-Ala2-Met5-enkephalinamide (DAMA), D-Ala2-Leu5-enkephalinamide (DADLE), Try-D-Thr-Gly-Phe-Leu-Thr, MR2034-TA, dextrorphan tartrate, U50,488H, levorphanol tartrate, methadone hydrochloride, and 1-methyl-4-phenyl-4-propionoxypiperidine induced spinal hypokinesia. The first 5 of these compounds caused spinal paralysis, whereas the other compounds and lower doses of the first 4 induced waxy catalepsy that was restricted to the hindquarters of rats. The paralysis induced by DAMA was not reversible by IT injections of 50 micrograms naltrexone, indicating, together with the paralytic effects of dextrorphan, that traditional opiate receptors are not involved in this behavioral effect. The spinal catalepsy induced by 0.26 mumol of DAMA was prevented by IT pretreatment with 10 micrograms of naltrexone. In view of this finding and the observation that spinal catalepsy can be induced by agonists of all opiate receptor classes, it seems likely that spinal catalepsy is produced by activation of specific opiate receptors, although the subtype remains to be established.

Animals↗
PubMed1988

Is substance P a primary afferent neurotransmitter for nociceptive input? I. Analysis of pain-related behaviors resulting from intrathecal administration of substance P and 6 excitatory compounds.

Intrathecal (i.t.) injection of substance P (SP), capsaicin, kainic acid, picrotoxin, strychnine, morphine, and L-glutamic acid in rats induced rhythmic scratching movements with the hindlimbs, biting, and, with some of these compounds, vocalization and myoclonic twitches. Although biting was directed to the dermatome corresponding to the injection site, scratching was aimed at anterior dermatomes. Presumably painful chemical stimulation produced by cutaneous and subcutaneous application of capsaicin or acetic acid never elicited scratching. Vocalization was never elicited by SP. When vocalization occurred following i.t. picrotoxin and morphine, it was correlated with myoclonic twitches rather than with scratching and/or biting. These findings indicate that scratching (a) is not pain-related and, (b) when elicited by the i.t. administration of the compounds listed above, does not result from activation of nociceptive primary afferent synapses.

Afferent Pathways↗
PubMed1988

Is substance P a primary afferent neurotransmitter for nociceptive input? II. Spinalization does not reduce and intrathecal morphine potentiates behavioral responses to substance P.

Scratching elicited by the intrathecal (i.t.) administration of substance P (SP) into the lumbosacral spinal cord of rats was not reduced by spinalization or i.t. pretreatment with the analgesic morphine. Spinalization also did not affect scratching elicited by i.t. kainic acid and potentiated scratching elicited by i.t. strychnine, picrotoxin, and L-glutamic acid. Intrathecal morphine did, however, reduce scratching elicited by i.t. strychnine and kainic acid. These findings demonstrate that the scratching elicited by i.t. SP and other neuroexcitatory agents is a spinally mediated response. That this response, when elicited by SP, is not inhibited by the analgesic morphine strongly suggests that SP does not elicit scratching by action at the primary afferent synapse and that the response is not indicative of pain.

Animals↗
PubMed1988

Is substance P a primary afferent neurotransmitter for nociceptive input? III. Valproic acid and chlordiazepoxide decrease behaviors elicited by intrathecal injection of substance P and excitatory compounds.

Intrathecal (i.t.) injections of substance P (SP) and kainic acid in rats produced rostrally directed scratches with the hindlimbs and caudally directed bites or licks. These behaviors, together with myoclonic twitches and vocalization, were also produced by I.T. morphine and strychnine. Intrathecal valproic acid (VA) significantly reduced all behaviors when these occurred spontaneously, and VA and chlordiazepoxide both reduced these behaviors when they were evoked by a light cotton swab tap to the lumbosacral region, in rats treated with the excitatory compounds. Since neither anticonvulsant affected the thermal or mechanical pain threshold at these doses, these results suggest that (a) the behaviors elicited by i.t. injection of the excitatory compounds are not responses to perceived pain, but rather the expression of a spinal convulsive-like state, and (b), since scratching and biting were the only behaviors produced by SP, this peptide is neither necessary nor sufficient for the elicitation of pain at the spinal level. Although our experiments do not rule out other roles for SP in pain processes such as that of a neuromodulator, it is unlikely that this compound is a traditional primary afferent neurotransmitter of pain.

Animals↗
PubMed1988

Is substance P a primary afferent neurotransmitter for nociceptive input? IV. 2-Amino-5-phosphonovalerate (APV) and [D-Pro2,D-Trp7,9]-substance P exert different effects on behaviors induced by intrathecal substance P, strychnine and kainic acid.

Intrathecal (i.t.) pretreatment with 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, diminished scratching with the hindlimbs, vocalization, biting or licking, and myoclonic twitches produced by i.t. strychnine, kainic acid, or morphine in rats. APV did not diminish these behaviors when produced by i.t. substance P (SP). The SP analogue [D-Pro2,D-Trp7,9]-substance P (DPDT) failed to affect any behaviors produced by all of these compounds at non-paralytic doses. At these doses, neither APV nor DPDT changed the thermal and mechanical pain thresholds. These results indicate that SP does not produce scratching at the primary afferent synapse in the spinal cord, that hindlimb scratching in rats is neither necessary nor sufficient to infer the presence of pain in rats, and that SP may not be involved uniquely, if at all, in the transmission of nociceptive information at the primary afferent synapse.

2-Amino-5-phosphonovalerate↗
PubMed1987

Reducing the risk of corneal graft rejection. A comparison of different methods.

Corneal graft rejection represents the leading cause of failure in corneal transplantation. Two of the major risk factors for graft rejection are previous sensitization, usually in the form of a previous rejected corneal graft and corneal vascularization. The major histocompatibility MHC antigens (HLA, A, B and DR) are the target of the corneal graft rejection process. Because HLA, A, B, and DR antigens have been found in the corneal epithelium, the corneal stroma, and the corneal endothelium, matching patients and donors would seem to reduce the incidence of rejection. The results of studies on HLA, A, B, and DR matching are discussed. Cyclosporin, a fungal by-product, prevents the proliferation of sensitized cytotoxic T cells. Its use topically in corneal transplant patients in a controlled series has also reduced the incidence of rejection. Its use systemically has also been tried in an effort to prevent corneal graft rejection.

Adult↗
PubMed1985

Spinal pain suppression mechanisms may differ for phasic and tonic pain.

The dorsolateral funiculus (DLF) spinal pathway has previously been identified as a major pathway involved in descending modulation of pain. While bilateral lesions of the DLF attenuated systemic morphine analgesia as measured by the tail-flick test, they failed to attenuate analgesia as measured by the formalin test. These results suggest that phasic and tonic pain, modeled by the tail-flick and formalin tests, respectively, may utilize different pain suppression mechanisms.

Animals↗
PubMed1985

Potentiation of morphine analgesia by the cholecystokinin antagonist proglumide.

Recent evidence has suggested that cholecystokinin (CCK) may act as a physiological opiate antagonist. Both the overlap of CCK and opiate systems within the central nervous system and the fact that exogenous CCK can antagonize opiate analgesia suggest that endogenous CCK systems interact with opiate-mediated pain inhibitory systems. In the present series of experiments, we examined the effect of the CCK receptor antagonist proglumide on various forms of morphine analgesia. We have observed that proglumide can potentiate morphine analgesia following systemic, intrathecal or intracerebral administration of these drugs. Endogenous CCK systems do not appear to be tonically active since neither systemic, intrathecal nor intracerebral proglumide typically produced measurable analgesia in the absence of morphine. These data suggest that CCK may be released in response to opiate administration and acts to return the organism toward its basal level of pain sensitivity. If such a hypothesis is in fact true, then CCK blockade may be of clinical value in the treatment of pain.

Analgesia↗
PubMed1985

Cholecystokinin antagonists selectively potentiate analgesia induced by endogenous opiates.

We have recently observed that exogenous sulfated cholecystokinin octapeptide (CCK) can antagonize various forms of opiate analgesia and that the CCK receptor blocker proglumide potentiates morphine analgesia. These observations, plus the similarity in the distribution of CCK and opiate systems, suggest that endogenous CCK may act as a physiological opiate antagonist. We have extended these initial studies by examining the effect of CCK antagonists on opiate analgesia produced by release of endogenous opiates (front paw footshock induced analgesia) and by intrathecal administration of D-Ala-methionine enkephalinamide, a stable analogue of an endogenous opiate. Additionally, the specificity of proglumide's effect was examined by testing the effect of this drug on various forms of non-opiate analgesia. This series of experiments demonstrate that CCK antagonists can markedly potentiate analgesia induced by endogenous opiates and provide strong support for the hypothesis that endogenous CCK systems can oppose the analgesic effects of opiates. Potentiation of analgesia by CCK receptor blockers appears to be selective for opiate systems since proglumide typically attenuated or had no effect on various forms of non-opiate analgesia. These data suggest that CCK blockers may be clinically useful for enhancing the analgesic effects of procedures such as acupuncture, which may be mediated by release of endogenous opiates.

Analgesia↗
PubMed1984

Effect of spinal cord lesions on convulsive activity induced by intrathecal morphine.

Non-specific convulsive behavior induced by intrathecal (IT) morphine microinjection appears to be tonically modulated by centrifugal pathways originating within the brain since the frequency of IT morphine-induced hindlimb seizures and myoclonic twitches are both increased following spinal transection. These effects on convulsant activity are dissociable by selective neural lesions. Bilateral dorsolateral funiculus lesions potentiate seizure activity whereas ventral funiculus lesions and, to a lesser extent, interruption of cerebral cortical influences enhance myoclonic twitch activity. These initial studies indicate that distinct supraspinal centers differentially modulate myoclonic and seizure activity and suggest that an understanding of these systems may have clinical implications for the control of convulsant activity.

Animals↗
PubMed1984

Muscarinic cholinergic mediation of opiate and non-opiate environmentally induced analgesias.

Previous studies have demonstrated that brief front paw shock and brief hind paw shock produce prolonged opiate and non-opiate analgesia, respectively. Additionally, opiate analgesia can be classically conditioned by using either front paw shock or hind paw shock as the unconditioned stimulus. However, beyond this point little is known regarding the neurochemistry of these phenomena. The present series of studies examined the potential involvement of nicotinic and muscarinic cholinergic systems in these 3 forms of environmentally induced analgesia. These experiments demonstrate that muscarinic cholinergic sites within the central nervous system are critically involved in the mediation of both hind paw (non-opiate) foot shock-induced analgesia ( FSIA ) and classically conditioned (opiate) analgesia since scopolamine, but not equimolar methylscopolamine, significantly attenuated analgesia. Furthermore, the primary muscarinic site(s) appears to exist at a supraspinal, rather than spinal, level since delivery of scopolamine directly to the lumbosacral cord produced, at most, only a slight decrease in analgesia. Nicotinic systems do not appear to be importantly involved in any of these forms of environmentally induced analgesias since mecamylamine had no effect on either front paw FSIA or hind paw FSIA and, at most, produced only a slight reduction in classically conditioned analgesia. These data and a review of the literature suggest that the critical cholinergic sites involved in hind paw FSIA exist within the caudal brainstem whereas cholinergic sites within more rostral brain levels probably mediate classically conditioned analgesia.

Analgesia↗
PubMed1984

Differential behavioral effects induced by intrathecal microinjection of opiates: comparison of convulsive and cataleptic effects produced by morphine, methadone, and D-Ala2-methionine-enkephalinamide.

Intrathecal (i.t.) microinjection of 400 micrograms of morphine in rats induces convulsive activity restricted to the hindlimbs. This activity is potentiated rather than antagonized by naltrexone, is potentiated in animals pretreated over 6 days with increasingly higher systemic doses of morphine, and is potentiated and prolonged by high thoracic spinalization . Similar to morphine, convulsive spinal activity could also be elicited with i.t. injection of the non-opiate convulsant penthylenetetrazol (PTZ). However, methadone, D-ala2-methionine-enkephalinamide (DALA), or naltrexone, injected i.t. at equimolar doses with morphine did not produce similar convulsive behavior. DALA and methadone rather produced pronounced spinal catalepsy. It was concluded: that the spinal convulsive action of morphine is not mediated by specific opiate receptors; and that the spinal cord may be one of the sites where high doses of systemically administered morphine may produce convulsions.

Animals↗
PubMed1984

Cataleptic effects of opiates following intrathecal administration.

Intrathecal (i.t.) administration of D-ala2-methionine-enkephalinamide (DALA) and methadone induces pronounced hindlimb catalepsy in rats. DALA is more potent than methadone in inducing this behavior and catalepsy induced by both compounds is partially blocked by prior treatment with naltrexone. Intrathecal morphine induces convulsive hindlimb activity at doses of 25, 100 and 400 micrograms. However, only the highest dose produces indications of cataleptic behavior. It is suggested that whereas the convulsive behavior induced by i.t. morphine is not mediated by specific opiate receptors, catalepsy induced by all 3 compounds is.

Animals↗