Complex role of peroxisome proliferator activator receptors (PPARs) in nociception
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Rashid Giniatullin
,
Geneviève Bart
1 Peroxisome proliferator activator receptor (PPAR) signalling
In this issue of the Scandinavian Journal of Pain, Okine et al. report the analgesic action of the synthetic peroxisome proliferator activator receptor-alpha (PPARα) agonist WY-14643 on nociceptive spinal neuronal firing in a rodent model of neuropathic pain [1]. The search for an efficient treatment of neuropathic pain has been rather challenging and the demonstration that new targets can be found is very encouraging. PPARα is a very promising target because contrary to many other anti-nociceptive treatments, its activation does not seem to be associated with any undesirable effect but rather is linked to several more broad benefits. It has been for instance, associated with lowering of inflammation [2], and improvement of cognitive functions in models of cognitive impairment [3]. Moreover, it was also shown not to induce tolerance, which is a common problem in chronic pain treatment [4].
The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors best characterized for their actions in metabolism and oxidative stress regulation. The PPAR family includes PPARα, PPARβ/δ and PPARγ all of which are expressed at different levels by microglia, astrocytes, neurons and oligodendrocytes [5]. PPARs het- erodimerize with the Retinoid X receptor to bind DNA on the PPAR response element (PPRE) and initiate gene transcription [6], several co-factors like PGC1-alpha, CBP/p300, SERC1 are necessary for further fine-tuning of tissue-specific effects. PPRE is highly conserved in different species, suggesting a fundamental role for the pathways it activates in a variety of fundamental biological processes. In addition to these genomic effects, receptor-like almost instantaneous responses (within minutes), independent of gene activation have also been described (reviewed in [7]), consistent with the earlier finding that a fraction of the PPARα proteins is located at the cell membrane [8].This novel observation added even more complexity to the previous canonical vision on genomic PPAR signalling.
The field of PPAR signalling has been rapidly expanding following the discoveries of endogenous ligands and the development of new subtype specific agonists but, till recently, it has been mostly directed to the study of metabolic and vascular disorders [9].
2 PPARα in nociception
It has been found recently that PPARα also plays an important anti-nociceptive role in the nervous system [4], which is clearly demonstrated in PPARα knockout mice, by their enhanced sensitivity to a range of noxious and mechanical stimuli in neuropathic pain models [10].
This likely implies that PPARα is an activator of endogenous pathways involved in limiting excessive pain signalling. The endogenous PPARα agonist palmitoylethanolamide is able to activate and subsequently desensitize the pain transducing TRPV1 channels in the peripheral nociceptive sensory neurons [11]. This study and others also suggests that the anti-nociceptive effect is mediated via the rapid, non-genomic PPARα signalling pathway. All these data present PPARα as a multifaceted candidate pathway for the fine-tuning ofpain control. To date, much attention was paid to the role of PPAR in primary sensory neurons (peripheral nociception), which express a plethora of pain transducing molecules such as heat and capsaicin activated TRPV1 receptors.
Recent study by Okine et al. [1] adds new support for the role of PPARα in pain control and identifies novel spinal targets for pain processing. The authors show that intraperitoneal administration of the synthetic PPARα agonist WY-14643 attenuated key symptoms of neuropathic pain in rats. The authors also obtained original data suggesting, unlike previous views on the peripheral role of PPARα [8], the involvement of spinal neurons in nociceptive signal processing in spinal nerve ligation model of neuropathic pain. The principal significance of the latter relies on the rationale route of drug administrations to counteract spinally located neuropathic pain. Effective systemic administration of analgesic drugs targeting central or spinal neurons normally protected by the brain-blood barrier has an obvious advantage over intrathecal delivery. The synthetic PPARα agonist WY-14643 used in this study is also offering hope for other challenging pathologies like Alzheimer disease, epilepsy and neuroinflammation as it was shown to counteract Aβ-42 toxicity in neurons [12], to prevent nicotine-induced seizure [13] and to modulate infection [14] and stroke-induced neuroinflammation [15].
The new data by Okine et al. provide a better understanding of the multicomponent signalling pathways in chronic pain by its identification of a novel location of PPARα receptors mediated anti-nociception at the level of spinal cord. Moreover, they suggest a practical pharmacologic approach and spinal targets for the pain management. Importantly, this is done with the chronic neuropathic pain, which is often resistant to common analgesic treatments.
3 Conclusion and implications
The study of Okine et al. [1] presents a novel aspect of the antinociception mediated by the synthetic PPARα agonist at the level of spinal cord in the rodent model of the neuropathic pain. The findings highlight the role of the spinal nociceptive network employing PPARs in pain processing. While promising data were obtained here in the rodent model, optimization of the pharmacokinetics and pharmacodynamics along with chemical design/improvement of this or similarly acting PPAR agonists is required, however, on the long way to clinical use of these agents.
DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2015.06.004.
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Conflict of interest: No conflict of interest declared.
References
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© 2015 Scandinavian Association for the Study of Pain
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- Editorial comment
- Editorial comment on Helen Richardson’s and Stephen Morley’s study on “Action identification and meaning in life in chronic pain”
- Original experimental
- Action identification and meaning in life in chronic pain
- Editorial comment
- Editorial comment on Karlsson et al. “Cognitive behavior therapy in women with fibromyalgia. A randomized clinical trial”
- Clinical pain research
- Cognitive behaviour therapy in women with fibromyalgia: A randomized clinical trial
- Editorial comment
- Assessing insomnia in pain – Can short be good?
- Observational study
- The Swedish version of the Insomnia Severity Index: Factor structure analysis and psychometric properties in chronic pain patients
- Editorial comment
- Reliability of pressure pain threshold testing (PPT) in healthy pain free young adults
- Observational study
- Reliability of pressure pain threshold testing in healthy pain free young adults
- Editorial comment
- Qualitative research in complex regional pain syndrome (CRPS)
- Topical review
- Building the evidence for CRPS research from a lived experience perspective
- Editorial comment
- Complex role of peroxisome proliferator activator receptors (PPARs) in nociception
- Original experimental
- Systemic administration of WY-14643, a selective synthetic agonist of peroxisome proliferator activator receptor-alpha, alters spinal neuronal firing in a rodent model of neuropathic pain
- Editorial comment
- Evaluation of pain in children with communication difficulties: r-FLACC translated and validated in Nordic languages
- Clinical pain research
- Assessment of pain in children with cerebral palsy focused on translation and clinical feasibility of the revised FLACC score
- Clinical pain research
- The revised FLACC score: Reliability and validation for pain assessment in children with cerebral palsy
- Editorial comment
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- Coping with painful sex: Development and initial validation of the CHAMP Sexual Pain Coping Scale
- Original experimental
- Spatial summation of thermal stimuli assessed by a standardized, randomized, single-blinded technique
