Rapid communication

Chronic naloxone results in prolonged increases in opiate binding sites in brain

Over the past two decades, the prescription of high dose opiate therapy has continued to accelerate in an attempt to treat patients with chronic pain. This presents a substantial challenge when patients on high dose opiate therapy require surgery, as opiate pain relief is a cornerstone of postoperative pain management. These patients have exceptionally challenging pain to control. This is likely due to downregulation of existing opiate receptors and the reluctance of clinicians to increase doses of opiates to exceptionally high levels to facilitate pain relief.

We hypothesize that using the method of ultra-rapid opiate detoxification (UROD), it would be possible to rapidly increase the number of opiate receptors and return patients to a more naive state, which would be susceptible to exogenous opiate administration. Validation of this hypothesis is supported by two mechanisms, the first of which are reports of patients that underwent UROD for opiate addition that subsequently suffer respiratory arrests when beginning to rapidly abuse opiates shortly after treatment. Additionally there are data demonstrating the tapering of opiate therapy prior to elective surgery results in better pain control.

In conclusion, we hypothesize that patients on chronic high dose opiates could obtain substantially better pain relief if they underwent UROD prior to surgery. This technique could be administered shortly before surgery and may dramatically improve the patients’ recoveries.

Nonsuicidal self-injury (NSSI), or the purposeful destruction of body tissue occurring without suicidal intent, is a perplexing behavior as it goes against the natural instinct to maximize pleasure and minimize pain. One possible reason that people engage in NSSI is to regulate affect. However, the exact mechanisms that cause NSSI to lead to reduced feelings of negative affect remain unclear. Due to its involvement in the regulation of pain and emotion, the endogenous opioid system has been proposed to mediate the affect regulation effects of NSSI. The authors review evidence from multiple literatures to support this claim. Based on the current research, it is proposed that (1) individuals who engage in NSSI have lower baseline levels of endogenous opioids, (2) NSSI releases endogenous opioids, and (3) opioids released during NSSI regulate affect. These predictions are discussed in terms of previous models and other functions of NSSI.

Migraine represents a central neural hypersensitivity. During an attack, migraine sufferers can be hypersensitive to normal levels of sound, light, smell and movement. Sensory processing dysfunction in the brain stem or diencephalic nuclei has been implicated. Most scientific migraine research has focused on neuronal function because of their central role in the processing, integration and transmission of sensory information. However the supporting glia, their receptors and their secreted mediators are now recognised as having an important role in neuronal function regulation. Activated microglia and astrocytes produce and release a variety of neuroexcitatory substances including nitric oxide, excitatory amino acids and proinflammatory cytokines. Spinal glial activation and the subsequent release of proinflammatory mediators initiate and maintain a range of enhanced pain states. The focus on neuronal function has ignored the potential contribution of glial cell activation to neural hypersensitivity and pain. If the central neuronal hypersensitivity associated with migraine represents glial cell activation, drugs that block glial cell activation and the subsequent release of neuroexcitatory substances could have therapeutic potential in both acute migraine treatment and migraine prophylaxis.

The role of endogenous opioid peptides in impairment of spatial performance due to epileptogenesis was examined. Animals were kindled by repeated injections of pentylenetetrazol (PTZ) (40 mg/kg, i.p.) in the presence or absence of the opioid receptor antagonist naloxone. Naloxone in different doses (1, 5 and 10 mg/kg, i.p.) was applied 30 min before each PTZ injection. Behavioral testing was assessed 24 h and 10 days after the last injection in separate groups of animals using Morris water maze. Our results showed that PTZ-induced kindling produced a significant impairment of spatial learning and memory as compared with controls and this effect was not due to the aftereffect of repeated seizures. Naloxone pretreatment in the course of kindling had no effect on seizures development, however it caused an improvement of spatial learning and memory performance in kindled rats. It is likely that the long-lasting changes in neuronal responsiveness associated with kindling led to a defect in the processing of spatial information. These data suggest that endogenous opioid peptides released in the hippocampus during kindling are at least in part responsible for impairment of spatial performance in kindled animals.

The Ca²⁺ channel blocker, nimodipine, increases the chronic naltrexone-induced supersensitivity to morphine analgesia in mice without affecting the density of up-regulated μ-opioid receptors. In the present study, the change in dihydropyridine-sensitive Ca²⁺ channels associated with chronic naloxone-induced supersensitivity to morphine analgesia was studied in rat whole-brain membranes using a radiolabeled Ca²⁺ channel blocker, [³H]PN200-110 {isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylate} (0.02–1.0 nmol/l). Rats were chronically treated with naloxone (1 mg/kg, i.p.), nimodipine (1 mg/kg, i.p.) or their respective vehicles twice daily for 10 days. On the 11th day, 16 h after the last injection of either nimodipine or naloxone, morphine (2 mg/kg, i.p.)-induced tail-flick analgesia was determined or rats were killed for the binding study. Chronic naloxone significantly potentiated (+84%) the morphine-induced analgesia. Chronic nimodipine also potentiated (+76%) morphine analgesia. In rats treated with nimodipine and naloxone, there was an additive increase (206%) in morphine analgesia. In binding studies, chronic naloxone resulted in a significant decrease (−39%) in the density (B_max) of [³H]PN200-110 binding with no change in K_d value when compared to the effect of chronic vehicle. Chronic nimodipine resulted in a slight but significant (+14.5%) increase in the B_max of [³H]PN200-110. However, when nimodipine was co-administered with naloxone, it not only reversed the down-regulation but actually up-regulated (+25%) [³H]PN200-110 binding with no change in K_d value. Our results show significant down-regulation of [³H]PN200-110 binding in association with naloxone-induced analgesic supersensitivity to morphine. The supersensitivity was also observed following chronic blockade of up-regulated Ca²⁺ channels by nimodipine. These results indicate an important role of L-type Ca²⁺ channel regulation in naloxone-induced analgesic supersensitivity to morphine.

Results of prior work indicate that (a) rats take stable, toxic levels of ethanol when they receive a daily regimen of limited opportunities to take both water and sweetened ethanol solution and (b) the combination of isradipine plus naltrexone persistently reduces those intakes. What are the effects of periodically missing doses of isradipine, naltrexone, or both? That is, what are the effects of differing levels of compliance? To get relevant information, rats were placed on a daily regimen, leading them to take, by choice, large amounts of ethanol (>2.0 g of ethanol per kilogram of body weight during 2 h a day). After being on this regimen for more than 60 days and after 28 days of no opportunity to take ethanol, 55 rats were divided into five groups. The opportunity to drink was then reinstated. One group received placebos, and another group received the combination of isradipine plus naltrexone daily. The other three groups received doses periodically, thereby conforming to good, moderate, and poor compliance. After abstinence, the intakes for rats receiving placebos rapidly returned to high levels. Intakes for rats receiving daily isradipine plus naltrexone did not return to high levels. The intakes for the other three groups were intermediate to intakes of the reference groups, corresponding to frequency of medication. When medication was not given, intakes approached placebo control levels, but the combination of isradipine plus naltrexone was effective when given subsequently. Daily dosing clearly is effective in reducing intakes, and suspension of dosing leads to higher intakes. A missed day of dosing, however, has limited consequences, provided that administration of medication is resumed.