Message Board

Substance P in the cerebrospinal fluid-contacting nucleus contributes to morphine physical dependence in rats

1. What is the action of Naloxone at the μ-opioid receptor? Why was it administered intracerebroventricularly (i.c.v) after achieving morphine dependence in the rats?

2. What did the SP-inhibitor (D-Pro2, D-Phe7, D-Trp9)-SP do to the rats (behaviorally and physiologically)?

3. 'SP in CSF-CN contributes to morphine physical dependence and withdrawal, and provide a novel pharmacological route for preventing or reversing opioid dependence.' What findings from the study support this? Do a little research and propose a future SP related treatment for opioid abuse.

4. (Opinion) In the event of an opiate overdose, Naloxone is used as the emergency resuscitation drug. Currently it is only available by prescription, but numerous studies across the country are investigating the benefit of making it available to the public (over the counter as a nasal spray). Are you in favor or opposed?

At the μ-opioid receptor, naloxone acts as a competitive antagonist. It has a very high affinity for the μ-opioid receptor, and when it binds, symptoms of withdrawal quickly manifest. It was administered intracerebroventricularly (i.c.v) to morphine-dependent rats to determine the types of symptoms rats exhibit when experiencing morphine withdrawal symptoms, and it was found that irritability, shaking like a wet dog, teeth chattering, diarrhea, salivation, abnormal positioning and weight loss were common displays of experiencing withdrawal.
Upon injection of naloxone in morphine-dependent rats, SP concentration in the hypothalamus and midbrain was found to spike at the height of their withdrawal experience. Substance P (SP) within the brain is itself increased by morphine dependence, and it is thought that SP plays a role in both developing physical dependence upon morphine and withdrawal. This being said, administration of the SP-inhibitor (D-Pro2, D-Phe7, D-Trp9)-SP was found to significantly reduce both morphine withdrawal and dependence by inhibiting binding of SP in the brain. After naloxone administration, when (D-Pro2, D-Phe7, D-Trp9)-SP was injected i.c.v, symptoms of withdrawal were attenuated and PWT and TWL times were increased, showing that the rats could tolerate more pain (allodynia) after being treated with (D-Pro2, D-Phe7, D-Trp9)-SP than before.
The team that wrote this report provided the evidence cited above to give credence to their hypothesis that SP in CSF-CN causes physical dependence upon morphine. As far as an SP-related treatment for opioid abuse, since SP does seem to be an important factor in developing a dependence upon morphine, research could be done to see if it has impacts upon addiction for other opioid drugs and narcotics. If it did, SP antagonists such as (D-Pro2, D-Phe7, D-Trp9)-SP could be used to help treat patients while weaning them off of opioid and narcotic drugs or, in the case of patients who must take these types of drugs for long periods of time (for pain or other reasons), make the process of getting off of the drug easier. Instead of using an antagonist, a type of enzyme could also be used that breaks down SP so that less of it would exist in the brain, which could lead to decreased withdrawal symptoms and dependency. This would have to be thoroughly tested, though, since SP serves other functions in the brain (such as regulation of vomiting and nociception). An appropriate manner of drug delivery would have to be found, as well, to make sure the drug could both access the brain and get released in the correct area of the brain. It could be that such a treatment would have to remain i.c.v injection-only and a patient undergoing such treatment would have to visit a specialist every so often to receive the injection.
OTC naloxone is an intriguing thought in that it is possible that more overdose patients could be saved if someone were able to treat them in time, but at the same time, naloxone is a very powerful drug and, if used inappropriately, could have some unwanted side-effects, including (as quoted from the Wikipedia article) ?change in mood, increased sweating, nausea, nervousness, restlessness, trembling, vomiting, allergic reactions such as rash or swelling, dizziness, fainting, fast or irregular pulse, flushing, headache, heart rhythm changes, seizures, [and] sudden chest pain.? As much as naloxone could help overdose victims outside of the immediate reach of emergency medical services, it appears that it could be dangerous to make available OTC. People could get confused or misinformed and use the drug for non-intended purposes which could lead to more harm being done than good. For these reasons, I?m hesitant to say naloxone would be a good candidate for OTC-status, but I?m definitely interested in seeing the results of the mentioned studies.

Naloxone is a drug typically administered to counter the effects of overdose of opiates such as morphine. As Clementine said, it is an antagonist that blocks the u-opioid receptors. When these receptors are blocked, withdrawal symptoms are shown. It was administered to rats intracerebroventricularly so the effects of withdrawal of these animals could be determined and compared later on. This simulated withdrawal in an effective controllable manner.

The SP-inhibitor (substance P) would reduce the severity of withdrawal symptoms in the rats. SP is often associated with pain. When SP-inhibitor (D-Pro2, D-Phe7, D-Trp9)-SP reduced the morphine dependence in these rats and made their withdrawal less intense. This shows, along with data from the experiment, that substance P was in high concentrations during withdrawal. It is clear that when these are inhibited, the withdrawal is also.

'SP in CSF-CN contributes to morphine physical dependence and withdrawal, and provide a novel pharmacological route for preventing or reversing opioid dependence.' This is demonstrated throughout the whole experiment as their hypothesis was proven correct. Since rats peaked at concentration of Substance P during the height of their withdrawal and since SP inhibitor (D-Pro2, D-Phe7, D-Trp9)-SP reduced withdrawal symptoms this was proven. As Clementine said, these drugs may be effective as drug therapy treatment. As long as someone is committed to treatment and if during this time they experience extreme withdrawal, it would be possible to administer these SP inhibitors to make withdrawal more comfortable. If safe amounts could be calculated, this would be effective in administration to those who have been taking morphine for a long time, or those who use other drugs such as heroin perhaps.

I personally do not believe it would be a good idea to make naloxone an over the counter drug. I think this would in some ways, condone recreational drug use, or rather, abuse. If this is a treatment for those who are overdosing, that would somewhat say "oh hey, its okay if we overdose, I've got some medicine that will fix it right here ready to go." There are also negative side effects to naloxone, clearly shown above in Clementine's response. If someone is overdosing on drugs, they should be aware that if medical services are contacted, they have a chance to be resuscitated, though having it over the counter would give opportunities for misuse, and the person could end up dying anyway.

Naloxone is a drug administered to counter the effects of opioid overdose. It functions as a competitive antagonist at u-opioid receptors. The rapid binding of these receptors often produces withdrawal symptoms. Naloxone is a fairly large chemical that cannot pass the Blood-Brain Barrier and thus was injected intracerebroventricularly (i.c.v). This type of injection also served to deliver the drug to it intended targets in the CSF-CN. This allowed researchers to observe the effects of opioid withdrawal in rats.

During withdrawal, Substance P was observed in large concentrations. The neuropeptide is related to pain and the transmission of pain sensations to the CNS from the periphery. In the presence of Naloxone, the concentration of SP increased in the rats CSF. The experiment was aimed at discerning the purpose of SP in morphine addiction and withdrawal. The injection of SP-inhibitors reduced the symptoms of opioid withdrawal (or at least morphine) and also reduced pain transmission (as observed in the Paw Withdrawal test and the Thermal Withdrawal test).

The findings in the study do not directly correlate the Substance P with morphine withdrawal and addiction. Upon the admission of SP inhibitors, the ability of the rat to feel pain is reduces, effectively mirroring the effect of morphine. But I do not see how this directly correlates to the idea that SP is related to dependence. However, as shown in the experiment, the drug does reduce the side effects of opioid withdrawal, the reduction of symptoms that were observed through the injection of Naloxone. I think the drug can be combined with other treatments to treat opioid withdrawal, but I also believe there to be more to addiction that this one neuropeptide. I do not see this as an aid to inhibit dependence but as stated by Clementine and Hannah, it can be used to reduce more severe withdrawal in highly dependent patients. This could hasten their ability to recover and to learn to avoid the drug.

I agree with Hannah, the availability of a drug that counters overdose might lead to an increase in the usage of the drugs from which the overdose is derived. Clementine outlined the side effects from said drug and I think the general public might overlook said effects when it comes time to administer. Also, Naxalone is derived from the controlled substance Thebaine. This substance is found naturally in opioids and is regulated internationally. It is nearly identical to Oxymorphone, an opioid analgesic similar to morphine but lacking in the severity of euphoria and sedation. The ability for a garage chemist to manipulate, or even attempt to manipulate the drug in order to sell illegally is very possible. At the current time, I would disagree with making Naloxone available to the public.

Naloxone unquestionable holds the potential to decrease opioid overdoses. It acts as a morphine antagonist. Thus the administration of this drug prevents morphine binding to its μ-opioid receptors, hence inhibiting the activation of the receptor?s G-coupled proteins, and preventing any form of second messenger cascade. Therefore, intracerebroventricular administration of naloxone to morphine addicts the rushes body into a state to withdrawal in the absence of morphine binding.

It follows of course that naloxone could decrease opioid overdoses via this mechanism. However, naloxone can be accompanied by severe side effects: dizziness, heart rhythm changes, seizures, severe allergic reactions and most notably hypoventilation. For this reason I feel naloxone should remain only available via prescription, not over the counter. There is a high probability that you will need the assistance of a physician just from the severity of its side effects. Aftermath of the drug aside, the cause for taking naloxone, opioid addiction/overuse, in itself calls out for physician assistance. It should be available to rehab facilities, ERs, hospitals, individuals whom have discussed their need for it with a doctor. However, making it available over the counter seems to encourage opioid abuse. The over the counter status would allow you to 1) preemptively buy naloxone to keep nearby in case of an overdose and 2) allow you run to the store when an OD occurs. If it?s the latter, you should be devoting the time it takes to run to the store to get your friend to a hospital. If it?s the former, to be at the grocery store and pick up some naloxone ?just in case,? to me sounds like a declaration that you have a problem, and you should seek help.

Substance P, as this study showed, contributes highly to morphine dependency. Thus, when there?s substance P inhibition in a naloxone treated subject, as was the case with group B of this experiment, there is a decline of typical morphine withdrawal symptoms. Compared with the control, substance-P inhibited rats had significantly higher Paw Withdrawal Thresholds (PWTs) and Thermal Withdrawal Latency (TWL), i.e. the SP inhibited (D-Pro2, D-Phe7, D-Trp9)-SP rats were less sensitive to pain. Additionally, in terms of quantifiable withdrawal symptoms, the SP-inhibited rats experienced significantly fewer episodes of teeth chatting, wet dog shakes, and diarrhea than SP-active rats. SP inhibited rats also experienced significantly less weight loss during the withdrawal period.

While the claim that substance P in CSF-CN supplements morphine physical dependence and withdrawal is in accordance with this data, I am intrigued as to how we know this correlation between SP-inhibition and decreased morphine withdrawal represents causation. The proposed mechanism for SP control does seem probable, that SP causes continuing neuronal membrane depolarization via receptor interaction or altering the CSF?s composition, which could result in long-term potentiation. Additional research should further examine the specifics of SP?s physiological pathways, possibly involving immunoassays before and after administration of substance P, in order to know what other chemical pathways it affects.