Pain
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Forebrain medial septum region facilitates nociception in a rat formalin model of inflammatory pain.
The medial septum is anatomically and functionally linked to the hippocampus, a region implicated in nociception. However, the role of medial septum in nociception remains unclear. To investigate the role of the region in nociception in rats, muscimol, a GABA agonist, or zolpidem, a positive allosteric modulator of GABA(A) receptors, was microinjected into medial septum to attenuate the activity of neurons in the region. ⋯ The reduction was accompanied by a decrease in formalin-induced expression of spinal c-Fos protein that serves as an index of spinal nociceptive processing. The drug effects on nociceptive behaviors were without overt sedation and were distinct from the effects observed after septal lateral microinjections. Taken together, these findings suggest that the activation of medial septum is pro-nociceptive and facilitates aspects of central neural processing underlying nociception.
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The management of neuropathic pain is unsatisfactory, and new treatments are required. Because the sensitivity of a subset of fast-conducting primary afferent nociceptors is thought to be regulated by the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, selectively targeting mTORC1 represents a new strategy for the control of chronic pain. Here we show that activated mTOR was expressed largely in myelinated sensory fibers in mouse and that inhibiting the mTORC1 pathway systemically alleviated mechanical hypersensitivity in mouse models of inflammatory and neuropathic pain. ⋯ Also, there was no evidence for neuronal toxicity after repeated systemic treatment with CCI-779. Additionally, we show that acute and chronic i.p. administration of Torin1 (20 mg/kg), a novel ATP-competitive inhibitor targeting both mTORC1 and mTORC2 pathways, reduced the response to mechanical and cold stimuli in neuropathic mice. Our findings emphasize the importance of the mTORC1 pathway as a regulator of nociceptor sensitivity and therefore as a potential target for therapeutic intervention, particularly in chronic pain.
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The endogenous cannabinoid (endocannabinoid) system plays an important role in fear-conditioned analgesia (FCA) and expression and extinction of conditioned fear. The hippocampus has an established role in both pain and conditioned fear and is a substrate for endocannabinoid activity. This study aimed to investigate the role of the endocannabinoid system in the ventral hippocampus (vHip) in FCA and in fear responding in the presence of nociceptive tone. ⋯ The URB597-induced enhancement of FCA was blocked by intra-vHip administration of the cannabinoid(1) (CB(1)) receptor antagonist/inverse agonist rimonabant. Intra-vHip rimonabant alone had no effect on the expression of FCA, and URB597 did not significantly alter formalin-evoked nociceptive behaviour in non-fear-conditioned rats. These data suggest an important role for the endocannabinoid system in the vHip in FCA, whereby levels of 2-arachidonoylglycerol and the FAAH substrates palmitoylethanolamide and anandamide are increased in rats expressing FCA, and pharmacological inhibition of FAAH in the vHip enhances this form of endogenous analgesia via a CB(1) receptor-dependent mechanism.
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Chronic pain in adults has been associated with early-life stress. To examine the pronociceptive effect of early-life stress, we evaluated cutaneous and muscle nociception and activity in muscle nociceptors in an animal model of neonatal stress, limited bedding, in the rat. In this neonatal limited bedding (NLB) model, litters are exposed to limited bedding between postnatal days 2 and 9, and controls to standard bedding. ⋯ Furthermore, administration of prostaglandin E(2) in skin as well as muscle produced markedly prolonged hyperalgesia, an effect prevented by spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase Cε (PKCε), a second messenger in nociceptors that has been implicated in the induction and maintenance of chronic pain. In electrophysiological studies, mechanical threshold of muscle nociceptors was reduced by ~31% and conduction velocity significantly increased (~28%). These findings indicate that neonatal stress induces a persistent hyperalgesia and nociceptor sensitization manifest in the adult and that the second messenger PKCε may be a target against which therapies might be directed to treat a chronic pain syndrome that is associated with early-life traumatic stress.