Poor sleep and pain: Does spinal oxidative stress play a role?

1 REM sleep deprivation and testing for mechanical hypersensitivity (“allodynia”)

For sleep intervention, the authors used a modified inverted flower pot technique by placing rats on a 7.5cm diameter pedestal surrounded by water. This set-up allows only those sleep stages where some muscular tonus is maintained; however, during REM sleep muscles become flaccid, the rat falls into the water and will wake up. Previous reports indicate that this technique deprives animals of 90–99% of REM sleep, but less than 10% of slow wave sleep [5]. This means that the experimental model mainly includes REM sleep deprived conditions, which may possibly weaken an extrapolation to sleep impairment in general. Also the selectivity of the intervention may be questioned since the REM sleep deprivation technique might as well induce general stress that could influence the findings. Nevertheless, the applied sleep intervention method relies on a long-established technique being well characterized in the literature, and is considered suitable for standardizing the experimental set-up as carried out by the present authors. For assessing mechanical hypersensitivity influenced by different experimental conditions, the investigators examined the withdrawal response to application of von Frey filaments to the hind paw of the rats. Hypersensitivity to previously innocuous tactile stimuli has been considered to resemble clinical “tactile allodynia” and is routinely used in animal pain research.

Before any pharmacological intervention, the authors confirmed previous findings that REM sleep deprivation as such induces pain hypersensitivity, and that these effects are dependent on the duration of the sleep impairment. In fact, the initial experimental set-up in this study provided results quite consistent with previous studies by the same research group [6,7,8], supporting the reliability of the experimental model for the tests of the study.

2 Intrathecal administration of antioxidants decreases “allodynia” in REM sleep deprived animals

For intrathecal drug administration, lumbar catheterization was performed, using a technique known to entail minor risk for neurological disturbances when used in experienced hands [9]. The investigators showed that the intrathecal injection of two different antioxidants produced similar and significant reductions in pain.

3 Intrathecal administration of reactive oxygen species (ROS) causes “allodynia”

On the other hand, when a ROS donor was injected intrathecally in normal-sleeping animals, pain hypersensitivity was produced to a similar degree as if they were REM sleep deprived. However, the ROS effect on pain did not occur if an antioxidant had been given beforehand.

These findings are worthy of note for several reasons. The sleep deprivation model is exclusively testing central mechanisms of pain, since there is no associated peripheral injury. The authors used two different nitroxide antioxidants (phenyl-N-tertbutylnitrone (PBN) or 4 hydroxy-2,2,6,6-tetramethylpiperidine-1 oxyl (TEMPOL)), which both showed significant alleviation in mechanical hypersensitivity, an observation further supported by clear dose–response effects. In a follow-up experiment, the intrathecal injection of a ROS donor (tert-butyl-hydroperoxide (t- BOOH)) into control animals mimicked the pain hypersensitivity patterns observed in REM sleep deprived rats. Furthermore, this ROS-induced pain could be virtually abolished if the animal was pretreated with TEMPOL. This latter observation is similar to the findings in a very recently published paper by Yowtak et al. [3], who injected t-BOOH intrathecally in control mice and observed a dose-dependently induced mechanical hyperalgesia. In fact, recent studies using in vivo and in vitro assays provide strengthened indications that increased ROS in spinal cord is involved in hyperalgesia in interaction with other mechanisms [3,8,10], and that ROS involvement takes place in various experimental models, including REM sleep deprivation.

4 Leading the way to more target-specific pain therapies possible

The present work of Wei et al. is contributing to a growing understanding of spinal mechanisms of pain transmission and hyperalgesia – and how treatment interventions may alleviate pain perception in a targeted approach. The elucidation of pathophysiological mechanisms and the flexibility of such systems as influenced by experimental interventions create hopes for future therapies. More specifically, it reminds us of the current trends of target-specific therapies in various parts of medicine. This means that interacting molecules are more directly placed at the site of action in order to circumvent systemic effects. Such on-site delivery of an active substance should normally reduce systemic exposure and toxicity while allowing more efficacious active site concentrations.

5 Challenges in translating animal data into clinical pain research

In recent years, only one new drug for intrathecal pain treatment has been brought to the market, ziconotide [11]. It is acknowledged that this agent has limitations in terms of efficacy and safety, and there is certainly a need for new developments in this area, acting specifically on pain signal transmission in the spinal cord. Since chronic pain requiring intraspinal analgesia is considered as a rare condition, ziconotide was granted an orphan drug designation in EU in 2001, which offered incentives for its development into a useful drug. However, in the last 10 years there have been no further intrathecal treatments for chronic pain receiving an orphan registration, even though such designation can be applied for at any stage of drug development [12]. Given the limitations of the orphan registry, this lack of new such designations may nevertheless reflect shortcomings in the translational approach into clinical drug testing. This concern has also been recently reviewed and highlighted in IASP Clinical Updates, where the authors discuss the relative lack of success in translating data obtained in animal models into new analgesics [13]. Apparently, experimental data could be more effectively communicated by reporting more in detail, similar to clinical trials. More detailed accounting for all participating animals would be helpful, e.g. by flow diagrams showing the progress of participants through the experimental phases and explaining dropouts which commonly occur in animal research. Likewise, adverse events would be informative, but is rarely reported. Moreover, acute and short-term data that are common in animal experiments may have limited relevance for chronic conditions.

6 Antioxidants for pain relief?

The authors of the present paper conclude that compounds with antioxidant properties might prove useful in clinical conditions when treating pain hypersensitivity accompanied by sleep-deprivation. Generally, the use of antioxidants for pain relief has been disappointing in clinical trials, with the exception of reported effects in chronic pancreatitis [14]. Hyperalgesia associated with sleep deprivation is part of a vicious circle which would lend itself for a particular study design with regard to an analgesic trial. Antioxidants for oral administration are often safe substances for clinical testing which have led to many trials in various conditions with mixed results. Possibly, the present paper by Wei et al. may inspire to inquiries into targeted therapies on specific anatomic structures involved in pain control.