Pain
-
The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice were susceptible to bone cancer pain and moreover had an earlier onset of pain-related behaviours compared with cancer-bearing, wild-type mice. ⋯ However, the recent discovery of a P2X7 receptor splice variant expressed in the knockout mice used for this study complicates the interpretation of the results. The P2X7 splice variant receptor was detected in the spinal cord but not in osteoclasts of the P2X7R KO mouse. Further experiments are needed to elucidate the exact role of the P2X7 receptors in bone cancer pain.
-
Gout is characterized by the deposition of monosodium urate (MSU) crystals. Despite being one of the most painful forms of arthritis, gout and the mechanisms responsible for its acute attacks are poorly understood. In the present study, we found that MSU caused dose-related nociception (ED(50) [ie, the necessary dose of MSU to elicit 50% of the response relative to the control value]=0.04 [95% confidence interval 0.01-0.11]mg/paw) and edema (ED(50)=0.08 [95% confidence interval 0.04-0.16]mg/paw) when injected into the hind paw of rats. ⋯ Furthermore, the antagonism of histaminergic H1 and serotoninergic receptors decreased the edema, but not the nociception of MSU. Finally, the prevention of the tryptase activity was capable of largely reducing both MSU-induced nociception and edema. Collectively, the present findings demonstrate that MSU produces nociceptive and edematogenic responses mediated by TRPV1 receptor activation and mast cell degranulation.
-
Tissue injury during a critical period of early life can facilitate spontaneous glutamatergic transmission within developing pain circuits in the superficial dorsal horn (SDH) of the spinal cord. However, the extent to which neonatal tissue damage strengthens nociceptive synaptic input to specific subpopulations of SDH neurons, as well as the mechanisms underlying this distinct form of synaptic plasticity, remains unclear. Here we use in vitro whole-cell patch clamp recordings from rodent spinal cord slices to demonstrate that neonatal surgical injury selectively potentiates high-threshold primary afferent input to immature lamina II neurons. ⋯ This occurs in a widespread manner within the developing SDH, as incision elevated miniature excitatory postsynaptic current frequency in both GABAergic and presumed glutamatergic lamina II neurons of Gad-GFP transgenic mice. The administration of exogenous nerve growth factor into the rat hindpaw mimicked the effects of early tissue damage on excitatory synaptic function, while blocking trkA receptors in vivo abolished the changes in both spontaneous and primary afferent-evoked glutamatergic transmission following incision. These findings illustrate that neonatal tissue damage can alter the gain of developing pain pathways by activating nerve growth factor-dependent signaling cascades, which modify synaptic efficacy at the first site of nociceptive processing within the central nervous system.
-
Comparative Study
Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain.
Data on comparative safety of opioid analgesics are limited, but some reports suggest disproportionate mortality risk associated with methadone. Our objective was to compare mortality rates among patients who received prescribed methadone or long-acting morphine for pain. This is a retrospective observational cohort drawn from Department of Veterans Affairs (VA) health care databases, January 1, 2000, to December 31, 2007. ⋯ Multiple sensitivity analyses found either no difference in mortality between methadone and long-acting morphine or lower mortality rates among patients who received methadone. In summary, we found no evidence of excess all-cause mortality among VA patients who received methadone compared with those who received long-acting morphine. Randomized trials and prospective observational research are needed to better understand the relative safety of long-acting opioids.