Allopregnanolone and Progesterone in Experimental Neuropathic Pain: Former and New Insights with a Translational Perspective.

In the last decades, an active and stimulating area of research has been devoted to explore the role of neuroactive steroids in pain modulation. Despite challenges, these studies have clearly contributed to unravel the multiple and complex actions and potential mechanisms underlying steroid effects in several experimental conditions that mimic human chronic pain states. Based on the available data, this review focuses mainly on progesterone and its reduced derivative allopregnanolone (also called 3α,5α-tetrahydroprogesterone) which have been shown to prevent or even reverse the complex maladaptive changes and pain behaviors that arise in the nervous system after injury or disease. Because the characterization of new related molecules with improved specificity and enhanced pharmacological profiles may represent a crucial step to develop more efficient steroid-based therapies, we have also discussed the potential of novel synthetic analogs of allopregnanolone as valuable molecules for the treatment of neuropathic pain.

Progesterone prevents nerve injury-induced allodynia and spinal NMDA receptor upregulation in rats.

BACKGROUND: Peripheral nerve injury-evoked neuropathic pain still remains a therapeutic challenge. Recent studies support the notion that progesterone, a neuroactive steroid, may offer a promising perspective in pain modulation. OBJECTIVES: Evaluate the effect of progesterone administration on the development of neuropathic pain-associated allodynia and on the spinal expression of N-Methyl-D-Aspartate Receptor subunit 1 (NR1), its phosphorylated form (pNR1), and the gamma isoform of protein kinase C (PKCγ), all key players in the process of central sensitization, in animals subjected to a sciatic nerve constriction. METHODS: Male Sprague-Dawley rats were subjected to a sciatic nerve single ligature constriction and treated with daily subcutaneous injections of progesterone (16 mg/kg) or vehicle. The development of hindpaw mechanical and thermal allodynia was assessed using the von Frey and Choi tests, respectively. Twenty two days after injury, the number of neuronal profiles exhibiting NR1, pNR1, or PKCγ immunoreactivity was determined in the dorsal horn of the lumbar spinal cord. RESULTS: Injured animals receiving progesterone did not develop mechanical allodynia and showed a significantly lower number of painful responses to cold stimulation. In correlation with the observed attenuation of pain behaviors, progesterone administration significantly reduced the number of NR1, pNR1, and PKCγ immunoreactive neuronal profiles. CONCLUSIONS: Our results show that progesterone prevents allodynia in a rat model of sciatic nerve constriction and reinforce its role as a potential treatment for neuropathic pain.

Progesterone and the spinal cord: good friends in bad times.

In recent years, a growing list of publications point to the value of steroid hormones as an interesting option for the treatment of several type of lesions and diseases of the nervous system. Progesterone, well known for its role in pregnancy, has recently been shown to exert neuroprotective and promyelinating effects in both, the peripheral and central nervous system, including the injured spinal cord. Previous work from our laboratory has shown that progesterone actions in experimental models of spinal neurodegeneration or injury may involve the modulation of brain-derived neurotrophic factor, a neurotrophin with important implications in neuronal survival and axonal regeneration. The spinal cord is target for progesterone since neurons and glial cells express the intracellular receptors for this neuroactive steroid. However, the presence in the spinal cord of new membrane receptors and the enzymes involved in progesterone metabolism to its reduced derivatives, which modulate the activity of neurotransmitter receptors, suggest that progesterone actions involve pleiotropic mechanisms. Our recent data uncovering several molecular events may help to understand the protective and promyelinating actions of progesterone and further support the role of this steroid as a promising therapeutic agent for neurotrauma and/or neurodegenerative diseases.

Neuropathic pain and temporal expression of preprodynorphin, protein kinase C and N-methyl-D-aspartate receptor subunits after spinal cord injury.

Central neuropathic pain is refractory to conventional treatment and thus remains a therapeutic challenge. In this work, we used a well-recognized model of central neuropathic pain to evaluate time-dependent expression of preprodynorphin (ppD), protein kinase C gamma (PKCgamma) and NMDA receptor (NMDAR) subunits NR1, NR2A and NR2B, all critical players in nociceptive processing at the spinal level. Male Sprague-Dawley rats were subjected to spinal hemisection at T13 level and sham-operated rats were included as control animals. The development of hindpaw mechanical allodynia was assessed using the von Frey filaments test. Real time RT-PCR was employed to determine the relative mRNA levels of NMDAR subunits, ppD and PKCgamma in the dorsal spinal cord 1, 14 and 28 days after injury. Our results show that, coincident with the allodynic phase after injury, there was a strong up-regulation of the mRNAs coding for ppD, PKCgamma and NMDAR subunits in the dorsal spinal cord caudal to the injury site. The present study provides further evidence that these molecules are involved in the development/maintenance of central neuropathic pain and thus could be the target of therapeutic approaches.

Brain-derived neurotrophic factor: a possible intermediate of progesterone action in the injured spinal cord

Progesterone (PROG), a steroid classically associated with reproductive functions, also provides neuroprotection to the lesioned peripheral and central nervous system, including the spinal cord. The latter is a target of PROG, as neurons and/or glial cells express intracellular receptors as well as membrane receptors for PROG. When spinal cord injury (SCI) is produced at the thoracic level, several genes become sensitive to PROG in the region caudal to the lesion site. Although the molecular mechanisms implicated in PROG neuroprotection remain elusive, several reports point to neurotrophic factors, their receptors and signaling cascades as possible intermediates of steroid action. Indeed, a 3-day course of PROG treatment to the injured animals increased the mRNA of brain-derived neurotrophic factor (BDNF) and BDNF immunoreactivity in perikaryon and processes of motoneurons, while neuronal chromatolytic changes were strongly prevented. Interestingly, previous data demonstrated that BDNF mimics some of these PROG effects in the spinal cord, suggesting that BDNF and PROG may share common intracellular pathways. Furthermore, PROG enhancement of endogenous BDNF may provide a local trophic support and regulate in a paracrine or autocrine fashion the function of neurons and glial cells to prevent cellular death after injury.