Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain
Introduction
The International Association for the Study of Pain defines neuropathic pain as pain generated by a lesion or disease affecting the somatosensory system. Neuropathic pain may have multiple causes such as nerve injury, brain trauma, tumors, metabolic deficit, vascular infarction, surgical rhizotomy, thoracotomy, drug toxicity, infection, etc. The symptoms characterizing neuropathic pain include a chronic discomfort with burning sensation, sharp, stabbing or shooting pain, allodynia, hyperalgesia and/or hyperpathia. In 2008, a group of neurologists suggested to define neuropathic pain as the ‘pain arising as a direct consequence of a lesion or disease affecting the somatosensory system’ (Treede et al., 2008). Owing to its complex etiology and features, the treatment and management of neuropathic pain are extremely complicated (Magrinelli et al., 2013). Consequently, neuropathic pain, which is refractory to several analgesic drugs, belongs to the category of stubborn pain that constitute major health concerns generating suffering in millions of patients and serious socio-economical problems. Development of novel strategies to treat effectively neuropathic pain is an urgent medical need and a crucial challenge for biomedical researchers. Progress has been made over the past two decades in the management and treatment of neuropathic pain but the substances developed induce several side effects including dependence, tolerance, nausea, reflex dysfunctions, treatment-emergent nervousness, anorexia or stomach burning (Dworkin et al., 2010, Kingery, 1997, U S Food and Drug Administration website, 2000, Wolfe and Trivedi, 2004). Therefore, the characterization of novel effective analgesic and neuroprotective molecules exhibiting a safe toxicological profile may allow the development of innovative and efficient therapeutic strategies against neuropathic pain. After a brief historical recall of the knowledge about the involvement of steroids in pain modulation, the present paper reviews and discusses several data supporting the idea that the natural neurosteroid AP is a promising steroidal molecule to be used to develop effective and non toxic therapies against chronic neuropathic pain.
Section snippets
Historical knowledge on the role of steroidal compounds in pain modulation
Several endogenous molecules regulating neural activity and plasticity have been suggested as pivotal modulators of pain mechanisms. For instance, it is well documented that neurotransmitters such as glutamate, substance P, serotonin, gamma-aminobutyric acid (GABA) are involved in the regulation of nociceptive processes leading to pain sensation (Millan, 1999, Millan, 2002). It has also been demonstrated that inflammatory and/or neuropathic pain may depend on the action of cytokines and other
Biochemical description of AP and evidence for its production in pain neural pathways
The steroidal compound AP is a neuroactive metabolite of progesterone. AP belongs to the family of neurosteroids that includes bioactive steroids endogenously synthesized in neurons and/or glial cells (for reviews, Baulieu et al., 1999, Mensah-Nyagan et al., 1999). The biosynthesis of AP from progesterone requires the complementary activities of two key enzymes: 5α-reductase which converts progesterone into dihydroprogesterone and 3α-hydroxysteroid oxido-reductase (3α-HSOR) that produces AP
Impact of neuropathic pain on AP synthesis in the spinal pain circuit
To establish a direct link between spinal mechanisms controlling pain transmission and the local production of neurosteroids in the DH, we performed a multidisciplinary study using the rat experimental model of neuropathic pain generated by sciatic nerve ligatures (Bennett and Xie, 1988). The combination of molecular and biochemical approaches (quantitative real time polymerase chain reaction after reverse transcription, western blot, radioimmunoassay, pulse-chase experiments, high performance
Involvement of endogenous AP in the control of sciatic nerve injury-induced neuropathic pain
The direct effect exerted on nociception or pain sensation by endogenous AP produced in the spinal cord was thoroughly investigated using healthy and experimental rat models of sciatic nerve injury-induced neuropathic pain (Mensah-Nyagan et al., 2008, Mensah-Nyagan et al., 2009, Schaeffer et al., 2010a, Schaeffer et al., 2010b). In vivo injections of pharmacological agents in the intrathecal space were coupled to behavioral analyzes to assess thermal and mechanical pain sensitivity thresholds.
Preventive and corrective effect of AP against anticancer drug-induced neuropathic pain
Antineoplastic drugs, which inhibit or prevent the growth or development of malignant cells, are commonly used for cancer chemotherapy (Baker, 2003, El-Helw and Hancock, 2007, Moore and Pinkerton, 2009, Petit et al., 2006). However, their therapeutic efficacy is limited by a major dose-dependent side effect which is painful peripheral neuropathy (Antoine and Camdessanche, 2007, Dougherty et al., 2007, Gamelin et al., 2004, Ling et al., 2007a, Ling et al., 2007b, Polomano and Bennett, 2001).
Conclusion
Neuropathic pain is a chronic disorder having multiple causes and affecting millions of patients. Effective alleviation or treatment of this stubborn pain is an urgent medical need that requires particularly the development of safe strategies based on compounds devoid of toxic or severe side effects. The data discussed in the present review show the predominance of neuroprotective and analgesic effects of the natural neurosteroid AP in several experimental and preclinical models. In humans,
References (125)
- et al.
Strategies for improving the efficacy and therapeutic ratio of glucocorticoids
Current Opinion in Pharmacology
(2012) - et al.
Testosterone affects formalin-induced responses differently in male and female rats
Neuroscience Letters
(2004) - et al.
Sex hormones, central nervous system and pain
Hormones and Behavior
(2006) - et al.
Peripheral nervous system involvement in patients with cancer
Lancet Neurology
(2007) - et al.
Visceral pain: gender differences in response to experimental and clinical pain
European Journal of Pain
(2004) - et al.
Animal models of chemotherapy-evoked painful peripheral neuropathies
Neurotherapeutics
(2009) - et al.
Anti-inflammatory actions of steroids: molecular mechanisms
Trends in Pharmacological Sciences
(1993) - et al.
Soft steroids: a new approach to the treatment of inflammatory airways diseases
Pulmonary Pharmacology and Therapeutics
(2003) - et al.
CGRP receptors in the control of pain and inflammation
Current Opinion in Pharmacology
(2009) - et al.
A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man
Pain
(1988)
Anxiolytic effects of 3 alpha-hydroxy-5 alpha[beta]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor
Brain Research
Pharmacological enhancement of delta-subunit-containing GABA(A) receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice
Pain
Quantitative assessment of tactile allodynia in the rat paw
Journal of Neuroscience Methods
Role of peri-axonal inflammation in the development of thermal hyperalgesia and guarding behavior in a rat model of neuropathic pain
Neuroscience Letters
Neurosteroids: biosynthesis and function of these novel neuromodulators
Frontiers in Neuroendocrinology
Sex differences in pain and analgesia: the role of gonadal hormones
European Journal of Pain
Corticosteroids suppress ectopic neural discharge originating in experimental neuromas
Pain
Dysfunction in multiple primary afferent fiber subtypes revealed by quantitative sensory testing in patients with chronic vincristine-induced pain
Journal of Pain and Symptom Management
Recommendations for the pharmacological management of neuropathic pain: an overview and literature update
Mayo Clinic Proceedings
Treatment of metastatic gestational trophoblastic neoplasia
Lancet Oncology
Glucocorticoids and treatment of prostate cancer: a preclinical and clinical review
Urology
Sex differences in opioid analgesia: clinical and experimental findings
European Journal of Pain
Specificity of female and male sex hormones on excitatory and inhibitory phases of formalin-induced nociceptive responses
Brain Research
Antinociceptive properties of neurosteroids I. Spinally-mediated antinociceptive effects of water-soluble aminosteroids
Pain
Antinociceptive properties of neurosteroids IV: pilot study demonstrating the analgesic effects of alphadolone administered orally to humans
British Journal of Anaesthesia
Testosterone reduces responsiveness to nociceptive stimuli in a wild bird
Hormones and Behavior
Systemic glucocorticoid therapy reduces pain and the number of endoneurial tumor necrosis factor-alpha (TNFalpha)-positive mast cells in rats with a painful peripheral neuropathy
Journal of Pharmacological Sciences
Effect of local methylprednisolone on pain in a nerve injury model. A pilot study
Regional Anesthesia
Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition
Pain
A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes
Pain
Methylprednisolone prevents the development of autotomy and neuropathic edema in rats, but has no effect on nociceptive thresholds
Pain
Distribution, metabolism and biological activity of deoxycorticosterone in the central nervous system
Brain Research
Venlafaxine hydrochloride (Effexor) relieves thermal hyperalgesia in rats with an experimental mononeuropathy
Pain
Behavioral and pharmacological description of oxaliplatin-induced painful neuropathy in rat
Pain
Behavioral and immunohistological assessment of painful neuropathy induced by a single oxaliplatin injection in the rat
Toxicology
Evidence for a monoamine mediated, opioid-independent, antihyperalgesic effect of venlafaxine, a non-tricyclic antidepressant, in a neurogenic pain model in rats
Pain
Neurosteroids: biochemistry and clinical significance
Trends in Endocrinology and Metabolism
Regulation of neurosteroid biosynthesis in the frog diencephalon by GABA and endozepines
Hormones and Behavior
Endogenous steroid production in the spinal cord and potential involvement in neuropathic pain modulation
The Journal of Steroid Biochemistry and Molecular Biology
Evidence for a key role of steroids in the modulation of pain
Psychoneuroendocrinology
The biological activity of 3alpha-hydroxysteroid oxido-reductase in the spinal cord regulates thermal and mechanical pain thresholds after sciatic nerve injury
Neurobiology of Disease
Allopregnanolone prevents and suppresses oxaliplatin-evoked painful neuropathy: multi-parametric assessment and direct evidence
Pain
The induction of pain: an integrative review
Progress in Neurobiology
Descending control of pain
Progress in Neurobiology
Antinociceptive properties of neurosteroids II. Experiments with Saffan and its components alphaxalone and alphadolone to reveal separation of anaesthetic and antinociceptive effects and the involvement of spinal cord GABA(A) receptors
Pain
Antinociceptive properties of neurosteroids III: experiments with alphadolone given intravenously, intraperitoneally, and intragastrically
British Journal of Anaesthesia
Antinociceptive profile of ring A-reduced progesterone metabolites in the formalin test
Pain
New evidence that both T-type calcium channels and GABAA channels are responsible for the potent peripheral analgesic effects of 5alpha-reduced neuroactive steroids
Pain
Selective regulation of 3 alpha-hydroxysteroid oxido-reductase expression in dorsal root ganglion neurons: a possible mechanism to cope with peripheral nerve injury-induced chronic pain
Pain
Spatiotemporal localization of injury potentials in DRG neurons during vincristine-induced axonal degeneration
Neuroscience Letters
Cited by (70)
Modulatory role of neurosteroidogenesis in the spinal cord during peripheral nerve injury-induced chronic pain
2024, Frontiers in NeuroendocrinologyA novel dual mode-of-action anti-hyperalgesic compound in rats which is neuroprotective and promotes neuroregeneration
2022, European Journal of PharmacologyPhysiopathological role of the enzymatic complex 5α-reductase and 3α/β-hydroxysteroid oxidoreductase in the generation of progesterone and testosterone neuroactive metabolites
2020, Frontiers in NeuroendocrinologyCitation Excerpt :For instance, in animals with neuropathic pain induced by peripheral nerve injury, the levels of THP are increased in the spinal cord, together with an increased expression and activity of 3α-HSOR (Gonzalez et al., 2019). In this case, the increase in the levels of THP and in the expression and activity of 3α-HSOR seem to be an adaptive response to control pain (Patte-Mensah et al., 2010; Patte-Mensah et al., 2014). In agreement with this interpretation, a decreased expression of 5α-R type 1 and type 2 in the dorsal spinal cord has been shown to be associated with the manifestation of allodynic behaviors in animals with spinal cord injury (Coronel et al., 2016).
Sex differences in steroid levels and steroidogenesis in the nervous system: Physiopathological role
2020, Frontiers in NeuroendocrinologyCitation Excerpt :In addition, THP ameliorates diabetic-induced thermal hyperalgesia and prevents cell apoptosis in spinal cord in the STZ model (Afrazi et al., 2014). The mechanisms of action of neuroactive steroids on neuropathic pain have been also characterized in other experimental models (Mensah-Nyagan et al., 2009; Patte-Mensah et al., 2014), where they regulate molecules involved in pain signaling, such as T-type calcium channels, GABA-A channels, P2X3 receptors, voltage-gated sodium channels and bradykinin signaling (Ayoola et al., 2014; Cho and Chaban, 2012). The inhibition of the local synthesis of THP in the spinal cord enhances neuropathic pain induced by sciatic nerve injury (Patte-Mensah et al., 2014).
Neurosteroids and neuropathic pain management: Basic evidence and therapeutic perspectives
2019, Frontiers in NeuroendocrinologyCitation Excerpt :To check this hypothesis, we evaluated the effects of 3α,5α-THP on behavioral, electrophysiological, histological and neurochemical parameters altered by VINC or OXAL treatment. Our results revealed that the prophylactic or corrective 3α,5α-THP treatment (4 mg/kg/2days) respectively prevented or abolished VINC or OXAL-induced mechanical hyperalgesia, mechanical allodynia and cold-allodynia (Meyer et al., 2010, 2011; Patte-Mensah et al., 2014; Fig. 1). Electrophysiological analyses allowed the determination of the effects of VINC or OXAL treatment on key functional parameters of the rat sciatic nerve including the conduction velocity (CV), the nerve action potential (NAP) onset and peak amplitude.