Pain
-
Macrophage infiltration to inflammatory sites promotes tissue repair and may be involved in pain hypersensitivity. Peroxisome proliferator-activated receptor (PPAR)γ signaling is known to regulate polarity of macrophages, which are often referred to as proinflammatory (M1) and antiinflammatory (M2) macrophages. We recently showed that the PPARγ agonist rosiglitazone ameliorated the development of postincisional hyperalgesia by increasing the influx of M2 macrophages to inflamed sites. ⋯ Administration of naloxone blocked the analgesic effects of rosiglitazone. We speculate that rosiglitazone alleviated the development of inflammatory pain, possibly through regulating the M1/M2 balance at the inflamed site by a PPARγ/HO-1-dependent mechanism. PPARγ signaling in macrophages may be a potential therapeutic target for the treatment of acute pain development.
-
In many patients, the sympathetic nervous system supports pain and other features of complex regional pain syndrome (CRPS). Accumulating evidence suggests that interleukin (IL)-6 also plays a role in CRPS, and that catecholamines stimulate production of IL-6 in several tissues. We hypothesized that norepinephrine acting through specific adrenergic receptors expressed on keratinocytes stimulates the production of IL-6 and leads to nociceptive sensitization in a rat tibial fracture/cast model of CRPS. ⋯ Based on these in vitro results, we returned to animal testing and observed that the selective β2-AR antagonist butoxamine reduced nociceptive sensitization in the CRPS model, and that local injection of the selective β2-AR agonist terbutaline resulted in mechanical allodynia and the production of IL-6 in the cells of the skin. No increases in IL-1β, TNF-α, or nerve growth factor levels were seen, however. These data suggest that in CRPS, norepinephrine released from sympathetic nerve terminals stimulates β2-ARs expressed on epidermal keratinocytes, resulting in local IL-6 production, and ultimately, pain sensitization.
-
Central poststroke pain (CPSP) is one of the most refractory chronic pain syndromes. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been demonstrated to provide moderate pain relief for CPSP. However, the mechanism underlying the pain relief remains unclear. ⋯ Intracortical facilitation in the responders was lower than in the controls and the nonresponders at baseline (P=.035 and P=.019), and significantly increased after rTMS (P=.039). There were no significant differences or changes in the other parameters. Our findings suggest that restoration of abnormal cortical excitability might be one of the mechanisms underlying pain relief as a result of rTMS in CPSP.
-
Voltage-gated Na(+) channels (Nav) are the targets of a variety of scorpion toxins. Here, we investigated the effects of Amm VIII, a toxin isolated from the venom of the scorpion Androctonus mauretanicus mauretanicus, on pain-related behaviours in mice. The effects of Amm VIII were compared with the classic scorpion α-toxin AaH II from Androctonus australis. ⋯ AaH II and Amm VIII reduced first spike latency and lowered action potential threshold. Amm VIII was less efficient than AaH II in increasing the gain of the firing frequency-stimulation relationship. In conclusion, our data show that Amm VIII, although less potent than AaH II, acts as a gating-modifier peptide reminiscent of classic α-toxins, and suggest that its hyperalgesic effects can be ascribed to gain-of-function of TTX-S Na(+) channels in nociceptors.
-
Current concepts of memory storage are largely based on Hebbian-type synaptic long-term potentiation induced by concurrent activity of pre- and postsynaptic neurons. Little is known about non-Hebbian synaptic plasticity, which, if present in nociceptive pathways, could resolve a number of unexplained findings. We performed whole-cell patch-clamp recordings in rat spinal cord slices and found that a rise in postsynaptic [Ca(2+)]i due to postsynaptic depolarization was sufficient to induce synaptic long-term potentiation (LTP) in the absence of any presynaptic conditioning stimulation. ⋯ The paired pulse ratio and the coefficient of variation remained unchanged in neurons expressing LTP, suggesting that this form of synaptic potentiation was not only induced, but also expressed postsynaptically. Postsynaptic depolarization had no influence on firing patterns, action potential shape, or neuronal excitability. An increase in [Ca(2+)]i in spinal lamina I neurons induces a non-Hebbian form of synaptic plasticity in spinal nociceptive pathways without affecting neuronal active and passive membrane properties.