Marta Silva

Pronociceptive changes in the activity of rostroventromedial medulla (RVM) pain modulatory cells in the streptozotocin-diabetic rat.

Neuropathic pain is one of the most frequent complications of diabetes. The increased neuronal activity of primary afferents and spinal cord neurons in streptozotocin (STZ)-diabetic rats increases the recruitment of the nociceptive ascending pathways, which may affect the activity of pain control circuits in the brain. This study aimed to characterize the electrophysiological responses of neurons of the rostroventromedial medulla (RVM), a key brainstem area involved in descending modulation of nociceptive neurotransmission at the spinal cord, in STZ-diabetic rats. Spontaneous and noxious-evoked activity of ON-like cells (pain facilitatory cells) and OFF-like cells (pain inhibitory cells) in the RVM were analyzed by single cell extracellular electrophysiological recordings in STZ-diabetic rats with behavioral signs of diabetic neuropathic pain 4 weeks after diabetes induction and in age-matched non-diabetic controls (CTRL). The electrophysiological analysis revealed an increase in the spontaneous activity of RVM pronociceptive ON-like cells in STZ-diabetic rats when compared to CTRL. On the contrary, the number of active antinociceptive OFF-like cells was significantly lower in the STZ-diabetic rats and their spontaneous activity was decreased when compared with CTRL. Overall, the changes in the activity of RVM pain modulatory cells in STZ-diabetic rats point to enhancement of descending pain facilitation. Based on similar results obtained at the RVM in traumatic neuropathic pain models, the changes in the electrophysiological responses of RVM in STZ-diabetic rats may account for exacerbated pain-like behaviors in diabetic neuropathy.

Endovanilloid control of pain modulation by the rostroventromedial medulla in an animal model of diabetic neuropathy.

The involvement of transient receptor vanilloid type-1 (TRPV1) channels in pain modulation by the brain remains understudied. The rostroventromedial medulla (RVM) plays a key role in conveying to the spinal cord pain modulatory influences triggered in higher brain centres, with co-existence of inhibitory (antinociceptive) and facilitatory (pronociceptive) effects. In spite of some reports of TRPV1 expression in the RVM, it remains unknown if endovanilloid signalling plays a direct role in local pain modulation. Here we used a model of diabetic neuropathy, the streptozotocin (STZ)-diabetic rat, to study the role of endovanilloid signalling in RVM-mediated pain modulation during chronic pain. Four weeks after diabetes induction, the levels of TRPV1 mRNA and fatty acid amide hydrolase (FAAH), a crucial enzyme for endovanilloid catabolism, in the RVM of STZ-diabetic rats were higher than control. The RVM of STZ-diabetic rats presented decreased levels of several TRPV1 endogenous ligands, namely anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Administration of capsaicin (a TRPV1 agonist) into the RVM decreased nociceptive behavioural responses in the inflammatory phase of the formalin test (phase 2). These findings suggest that diabetic neuropathy induces plastic changes of RVM endovanilloid signalling, indicating that TRPV1 may be a putative target for pain modulation in this chronic pain condition.

RETRACTED: Inhibition of spinal 5-HT3R reverted diabetes-induced mechanical hypersensitivity in a GABAAR-mediated neurotransmission-dependent manner

Spinal 5-HT3 receptor (5-HT3R) has been implicated in chronic pain development. The extent to which 5-HT3R contributes to spinal sensitization and diabetic neuropathic pain (DNP) remains elusive and the mechanisms subserving the effects of 5-HT3R activation on spinal pain processing during chronic pain are still unclear. In this study, we evaluated the contribution of spinal 5-HT3R to pain facilitation and spinal sensitization during DNP, exploiting the role of GABAAR-mediated neurotransmission and glial activation in the effects elicited by intrathecal administration of a 5-HT3R antagonist. Mechanical nociception was evaluated by paw pressure test in streptozotocin (STZ)-diabetic and control rats after intrathecal (i.t.) administration of a 5-HT3R antagonist (Y25130). The spinal activation of extracellular signal-regulated kinases (ERKs) pathway and the expression of 5-HT3R, glial fibrillary acidic protein (GFAP; marker of astroglia activation) and ionized calcium binding adaptor molecule 1 (IBA-1; marker of microglia activation) were evaluated at the peak maximum effect of Y25130. The involvement of GABAAR-mediated neurotransmission in the behavioral pain effect of Y25130, was assessed in STZ-diabetic animals receiving i.t. administrations of muscimol (GABAAR agonist). Intrathecal administration of Y25130 reverted mechanical hyperalgesia and decreased the activation of ERKs in STZ-diabetic rats, while no effects were observed in control animals. The spinal activation of GABAAR by i.t. administration of muscimol abolished Y25130-driven antinociception. The expression of IBA-1, GFAP and 5-HT3R was unaltered by treatment. These findings point to a GABA-mediated pronociceptive role of spinal 5-HT3R during DNP.

TRPV1 in pain control from the brain

Despite of the intense research confirming the funding Hippocratic idea that “Men ought to know that from the brain, and from the brain only, arise our(...) pains”, pain modulation from the brain remains a cuttingedge issue in neurobiology. It is now accepted that the brain has the capacity to modulate the magnitude of perceived pain, depending on individual and contextual factors (such as stress, anxiety or attention). Pain modulation from the brain is under a continuous balance between inhibition and facilitation. Increased descending facilitation appears to account for chronic pain installation. The periaqueductal gray (PAG) is a gateway control center that conveys to the spinal cord the modulatory inputs triggered from cortical and subcortical areas. The modulatory influences exerted by the PAG are typically relayed by the rostroventromedial medulla (RVM), an area that arbors neurons associated with pain inhibition or pain facilitation. Although pain modulation from the brain may differ accordingly to pain modality, an important role for the RVM in pain modulation has been ascribed [1]. While better known for its role in pain transduction in the periphery, recent reports proposed that the transient receptor potential vanilloid type 1 (TRPV1) may also participate in pain regulation from the brain. Noteworthy, Silva et al., 2016 [2] provided new insights about the role of TRPV1 in pain modulation from the brain by showing, for the first time, that the receptor plays a role in RVM-mediated pain control during chronic pain (namely in an animal model of metabolic neuropathy the streptozotocin diabetic rat). In this work, we demonstrate that mRNA levels of TRPV1 in the RVM of diabetic neuropathic animals increase about 30 times when compared to age-matched healthy control animals. This huge increase of TRPV1 in the RVM of diabetic rats seem to be accompanied by a doubling of the levels of fatty acide amide hydrolase (FAAH), an enzyme involved in the catabolism of several of the TRPV1 endogenous ligands. Although the activity of FAAH was not directly evaluated, this increase in FAAH expression is likely to have functional consequences, once endogenous TRPV1 ligands typically catabolized by FAAH decrease in the RVM of diabetic animals. The administration of a TRPV1 agonist in the RVM of diabetic neuropathic induced a decrease of nociceptive responses in diabetic rats but had no effect in healthy animals, which nicely matches the very low expression of TRPV1 detected in the RVM of these control animals. Altogether, these data support that the TRPV1 may play a role in descending modulation from the RVM during diabetic neuropathy by mechanisms that do not seem to be functionally relevant in heathy control conditions. Chronic pain is known to induce a plethora of plastic changes in the brain as a mechanism of adaptation to the continuous arrival of nociceptive input. We propose that upregulation of TRPV1 in the RVM of diabetic rats may represent an example of those processes. Neurobiologists that study the role of TRPV1 in the brain [3], have been thrilled by situations in which the low or almost undetectable levels of this receptor in baseline conditions increase during “stressful” conditions, as it appears to occur with the excessive transmission of nociceptive information during chronic pain. In the other side, an elegant previous study genetically modifying the TrpV1 locus to reveal its distribution and fate map suggested that expression of TRPV1 in some brain areas (namely the RVM) may be target of a developmental restriction. TRPV1 expression can, thus, exert a transient role in embryonic development of some brain areas, then decaying to undetectable levels postnatally [4]. Supporting this idea, recent studies showed that TRPV1 plays a key role during neuronal differentiation and neurogenesis. Although the precise mechanisms behind this interesting feature of TRPV1 remain to clarify, current research has been concentrating efforts in shedding light on the putative implications of TRPV1 in regeneration of injured neurons and its proadaptive network integration [5]. Inspired by these findings, we propose that chronic pain could Editorial