Articles: hyperalgesia.
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A burn is a severe injury, and the resulting pain can be very significant. Currently, opioids are the primary method of pain management, but these drugs have side effects; thus, it is of prime focus to research the mechanisms of pain formation and analgesic drugs. ⋯ TMP alleviates nociceptive transmission of burn-injury pain mediated by the P2X3 receptor.
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The peptide endothelin-1 (ET1), which was originally identified as a vasoconstrictor, has emerged as a critical regulator of a number of painful conditions, including inflammatory pain and tumor-associated pain. There is considerable pharmacological evidence supporting a role for endothelin A receptors (ET(A)) in mediating ET1-induced pro-algesic functions. ET(A) receptors are expressed in small-diameter nociceptive neurons, but also found in a variety of other cell types in peripheral tissues, including immune cells, keratinocytes, endothelial cells, which have the potential to modulate nociception. ⋯ Behavioural and pharmacological experiments showed that only late nociceptive hypersensitivity caused by ET1 is abrogated upon a loss of ET(A) receptors on nociceptors and further suggest that ET1-induced early nociceptive hypersensitivity involves activation of ET(A) as well as ET(B) receptors in non-neural peripheral cells. Furthermore, in the context of alleviation of cancer pain and chronic inflammatory pain by ET(A) receptor antagonists, we observed in corresponding mouse models that the contribution of ET(A) receptors expressed in nociceptors is most significant. These results help understand the role of ET(A) receptors in complex biological processes and peripheral cell-cell interactions involved in inflammatory and tumor-associated pain.
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The dynorphin-kappa opioid receptor (KOR) system regulates glial proliferation after sciatic nerve injury. Here, we investigated its role in cell proliferation following partial ligation of infraorbital nerve (pIONL), a model for trigeminal neuropathic pain. Mechanical allodynia was enhanced in KOR gene deleted mice (KOR-/-) compared to wild type mice. Using bromodeoxyuridine (BrdU) as a mitotic marker, we assessed cell proliferation in three different areas of the trigeminal afferent pathway: trigeminal nucleus principalis (Vp), trigeminal root entry zone (TREZ), and trigeminal ganglion (TG). ⋯ These results show that kappa opioid receptor system has different effects after pIONL in CNS and PNS: KOR activation promotes CNS astrocytosis and microglial or stem cell proliferation but inhibits macrophage proliferation in PNS. The trigeminal central root has a key role in the etiology and treatment of trigeminal neuralgia, and these newly identified responses may provide new targets for developing pain therapies.
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Methadone used for opioid dependence therapy is associated with increased pain sensitivity. This study aimed to investigate whether methadone administration lowers nociceptive threshold in adult male Sprague-Dawley (SD) rats, and if this threshold could be altered by the NMDA receptor antagonist memantine. Rats were implanted with osmotic pumps delivering 1mg/kg/day methadone (n=6), or saline placebo (n=6) (0.51 microl/h). ⋯ Paw withdrawal latency of rats treated with methadone co-administered with memantine did not differ significantly compared to methadone only (P>0.05). This demonstrates that methadone induces hyperalgesia in the SD rat yet this hyperalgesia resolves following discontinuation of methadone administration. Furthermore, memantine does not alter the development of methadone-induced hyperalgesia.
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The cooling agents menthol and icilin act as agonists at TRPM8 and TRPA1. In vitro, activation of TRPM8 by icilin and cold, but not menthol, is dependent on the activity of a sub-type of phospholipase A2, iPLA2. Lysophospholipids (e.g. LPC) produced by PLA2 activity can also activate TRPM8. The role of TRPA1 as a primary cold sensor in vitro is controversial, although there is evidence that TRPA1 plays a role in behavioural responses to noxious cold stimuli. In this study, we have investigated the roles of TRPM8 and TRPA1 and the influence of iPLA2 on noxious cold sensitivities in naïve animals and after local administration of menthol, icilin and LPC. The roles of the channels in cold sensitivity were investigated in mice lacking either TRPM8 (Trpm8-/-) or TRPA1 (Trpa1-/-). ⋯ The findings that iPLA2 inhibition blocked the development of cold hypersensitivity after administration of icilin but failed to affect menthol-induced hypersensitivity agree well with our earlier in vitro data showing a differential effect of iPLA2 inhibition on the agonist activities of these agents. The ability of LPC to induce cold hypersensitivity supports a role for iPLA2 in modulating TRPM8 activity in vivo. Studies on genetically modified mice demonstrated that the effects of icilin and LPC were mediated by TRPM8 and not TRPA1. In contrast, menthol-induced cold hypersensitivity was dependent on expression of TRPA1 and not TRPM8.