Henry J. Haigler

Morphine: ability to block neuronal activity evoked by a nociceptive stimulus.

Abstract The effect of morphine on the neuronal activity evoked by a nociceptive stimulus, a foot pinch, was studied in the dorsal raphe nucleus (DR) and in the mesencephalic reticular formation (MRF) of the rat. In the MRF and adjacent areas, neuronal firing was accelerated by the nociceptive stimulus. Morphine blocked this acceleration when administered either microintophoretically or i.v. Three lines of evidence indicate that this is a specific narcotic effect. First, naloxone, a specific narcotic antagonist, antagonized the effect of morphine. Secondly, two morphine agonists, oxymorphone and methadone, blocked the evoked neuronal acceleration like morphine when administered either microiontophoretically or i.v.; naloxone also blocked the effects of the two agonists. Finally, two non-opioid CNS depressants did not block the acceleration in neuronal firing even though microintophoretic ejection currents 2–5 times greater than those for morphine were used. In contrast, neuronal firing in the DR was rarely altered by the nociceptive stimulus or by morphine, administered either microiontophoretically or i.v. Furthermore, morphine did not affect the inhibition produced by 5-HT on neurons in the DR. It is concluded from this study that the MRF is a possible site of action for the antinociceptive effects of morphine. It is also concluded that morphine does not affect the spontaneous neuronal firing rate in the DR and that the DR is not a site of action of the antinociceptive effects of morphine when a foot pinch is used as the nociceptive stimulus.

Morphine: Effects on serotonergic neurons and neurons in areas with a serotonergic input

The hypothesis that morphine acts on the serotonergic system to produce analgesia is based on the previous observations that (1) lesions and stimulation of midbrain raphe nuclei after the threshold to nociceptive stimuli; (2) morphine alters the turnover of serotonin (5-hydroxytryptamine; 5-HT). Microiontophoretic experiments were carried out to determine if morphine affected the firing rate of cells in five areas of the serotonergic system consisting of 5-HT containing neurons in the midbrain raphe nuclei (dorsal raphe and median raphe) or neurons in three areas (amygdala, optic tectum and subiculum) which are thought to receive a 5-HT input from the raphe nuclei. Morphine administered microiontophoretically slowed or inhibited the spontaneous neuronal firing in 34% of the cells studied in both the pre- and post-synaptic areas; systemically administered morphine gave similar results. However, the inhibition of neuronal firing by morphine in the five areas of the serotonergic system studied was not a specific narcotic effect because (1) it was not stereospecific; and (2) it was rarely blocked by naloxone. The inhibitory effect of morphine does not appear to be related to the analgesic effects of morphine because neuronal firing in the midbrain raphe nuclei and three possible postsynaptic areas was rarely altered by a nociceptive stimulus. It is concluded that (1) the analgesic effect of morphine is not related to an effect on neurons in the midbrain raphe nuclei and three areas which receive an identified 5-HT input; and (2) the effect of morphine on neurons in these five areas of the serotonergic system is not a specific narcotic effect.

Comparison of the analgesic effects of dimethyl sulfoxide and morphine.

Abstract : DMSO produces analgesia in rats on tests that typically only detect the analgesic effects of potent narcotic analgesic drugs (i.e. the hot-plate and tail-flick tests). There seem to be two components of this analgesic effect; one component related to a local effect and the other component related to a systemic effect. If only the feet are exposed to DMSO, the rat becomes analgesic on the hot-plate and tail-flick. If a greater surface body is exposed, the rat becomes analgesic on both the hot plate and tail flick indicating a central action, because the tail did not come into contact with the DMSO. In one study on patients the authors conclude that the analgesic effect of DMSO arises from a central, not local, analgesic effect. The analgesic effects of DMSO are not consistently blocked by naloxone indicating that these analgesic effects of DMSO are not consistently blocked by naloxone indicating that these analgesic effects of DMSO do not have the same mechanism of action as morphine.

A comparison of the analgesic and behavioral effects of [D-Ala2] met-enkephalinamide and morphine in the mesencephalic reticular formation of rats

Abstract [D-Ala 2 ]Met-enkephalinamide (DALA) injected intracerebrally (IC) at low doses into specific sites of the mesencephalic reticular formation (MRF), produced a profound, long-lasting analgesia that was blocked by naloxone, a specific opiate antagonist. Morphine was only half as potent as DALA because morphine, injected IC at similar sites in the MRF, yielded a comparable analgesia only when injected at twice the dose. The analgesic effects of morphine were also antagonized by naloxene. Both DALA and morphine produced specific behavioral effects. Naloxone blocked the behavioral effects of DALA, but not those produced by morphine.

Analgesia produced by direct injection of morphine into the mesencephalic reticular formation

Morphine administered intracerebrally (IC) (10 micrograms as the base on each side) into the MRF produced a significant dose dependent elevation of nociceptive threshold (i.e., analgesia) on the tail flick test and hemostat pinch test. However, morphine IC at lower doses had no analgesic effect. After morphine was injected IC (10 micrograms, bilaterally) into the MRF, naloxone, a specific narcotic antagonist, administered either IC at the same site (15 micrograms, bilaterally) or subcutaneously (10 mg/kg), antagonized the antinociceptive effects of morphine. Thirty percent of the animals given bilateral microinjection of 10 micrograms of morphine displayed hyperreactivity to mild stimuli. This hyperreactivity was not attenuated by large IC or systemic doses of naloxone. It was concluded that the MRF is a site where morphine may act to produce analgesia by a specific narcotic mechanism of action.

Paralemniscal reticular formation: Response of cells to a noxious stimulus

Extracellular single unit recordings were made in the paralemniscal reticular formation in adult male rats. A majority of the cells studied were characterized as nociceptive because a noxious stimulus evoked a change (either an increase or decrease) in their spontaneous firing rates. Norepinephrine (NE) administered microiontophoretically usually mimicked the response to the noxious stimulus (foot pinch). After a neuron had been characterized with respect to its response to NE and the noxious stimulus, horseradish peroxidase (HRP) was iontophoretically ejected from the micropipette. Following iontophoresis of HRP into the paralemniscal reticular formation, retrograde and orthograde labeling was observed in the periaqueductal gray and the nucleus raphe magnus. These data support a possible role of the paralemniscal reticular formation in an endogenous analgesic system.

Substance P, morphine and methionine-enkephalin: Effects on spontaneous and evoked neuronal firing in the nucleus reticularis gigantocellularis of the rat

A nociceptive stimulus (e.g., foot pinch) produced a significant increase in firing in cells in the nucleus reticularis gigantocellularis (NRGC) and surrounding areas of the rat brain. Substance P (SP), a putative nociceptive neurotransmitter, infrequently produced an increase in spontaneous neuronal firing when administered micro-iontophoretically to these areas. These data indicate that the NRGC is an area involved in nociception. However, SP does not appear to be the primary nociceptive neurotransmitter or neuromodulator in the NRGC because SP did not mimic or enhance the response to the nociceptive stimulus. Morphine (MS) and methionine-enkephalin (ENK), administered microiontophoretically, rarely had any effect on spontaneous neuronal firing or rarely modified the increase in neuronal firing evoked by the nociceptive stimulus. For this reason, the NRGC is apparently not an area where MS and ENK act directly to produce analgesia.

Effects of clonidine on neuronal firing evoked by a noxious stimulus

When norepinephrine was applied microiontophoretically to certain neurons in the pontine reticular formation of rats, it produced an increase in neuronal firing like that produced by noxious stimulation. Previous studies have shown that both noxious stimulus- and norepinephrine-evoked increases in neuronal firing are mediated by alpha-adrenoceptors. These neurons were unresponsive to non-noxious stimuli, suggesting that they might play a role in nociception. Microiontophoretic or systemic administration of the selective alpha 2-adrenoceptor agonist clonidine significantly attenuated noxious stimulus-evoked firing, but had little effect on firing evoked by norepinephrine. This effect of clonidine could be prevented by the alpha 2-adrenoceptor antagonists piperoxan and yohimbine. These antagonists, when given alone, increased noxious stimulus-evoked firing, but had no effect on firing evoked by norepinephrine. In contrast, the selective alpha 1-adrenoceptor antagonist ARC-239 (2-(2,4-(o-methoxyphenyl)-piperazin-1-yl)ethyl-4,4-dimethyl-1,3-(2 H,4) isoquinolindione dihydrochloride) attenuated both noxious stimulus- and norepinephrine-evoked firing. These data are consistent with the hypothesis that presynaptic alpha 2-adrenoceptors modulate the release of norepinephrine. Furthermore, these data suggest that the pontine reticular formation is one site at which clonidine could act to produce analgesia.

Effects of serotonin and morphine on spontaneous and evoked firing of nociceptive neurons in the trigeminal spinal nucleus of rats

Spontaneously firing neurons that were responsive to noxious face pinch or noxious heat were studied in the trigeminal spinal nucleus of the rat brain. These neurons responded with either an increase or decrease in firing rate. In these neurons serotonin (5-hydroxytryptamine; 5-HT) apparently acts through two mechanisms to attenuate the response to a noxious stimulus. One mechanism is mimicked by morphine; these two drugs block the response to the noxious stimuli without having a consistent effect on spontaneous firing. The effects of the two drugs were somewhat selective depending on the noxious stimulus used and the effect of the noxious stimulus; morphine and 5-HT were more effective in blocking the increase in firing rate evoked by the face pinch but 5-HT and morphine were more effective in blocking the decrease in firing rate evoked by the noxious heat stimulus. Interestingly, the direction of the response to a particular noxious stimulus frequently predicted whether or not both morphine and 5-HT would act on the same or different neurons. A second mechanism by which 5-HT, but not morphine, acted was to change the spontaneous firing in a direction opposite that evoked by the noxious stimulus. This type of effect apparently modulated the response to a noxious stimulus by changing the spontaneous firing rate such that a noxious stimulus had to be more intense before it could significantly alter the neuronal firing in the opposite direction. Morphine occasionally produced a change in firing pattern in neurons; this effect remains to be documented more extensively.

DMSO (dimetyl sulfoxide), morphine and analgesia

Abstract DMSO was compared to morphine in rats to determine its relative analgesic effects. DMSO produces analgesia that is comparable in magnitude to morphine although its duration (6–7 hrs) is longer than that of morphine (≤ 2 hrs). DMSO apparently produced analgesia both by an action at the site at which it was administered as well as at a site that was remote to the site of administration. The mechanism of action of DMSO is apparently different from that of morphine because naloxone, a specific narcotic antagonist, does not block the analgesic effect of DMSO. However, DMSO has toxic effects such as hematuria (bloody urine). Therefore, the toxicity observed may restrict the clinical usefulness of DMSO as an analgesic drug.