Pain
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Agonists to subtype C of the Mas-related G-protein-coupled receptors (MrgC) induce pain inhibition after intrathecal (i.t.) administration in rodent models of nerve injury. Here, we investigated whether tolerance develops after repeated MrgC agonist treatments and examined the underlying mechanisms. In animal behavior studies conducted in male rats at 4 to 5 weeks after an L5 spinal nerve ligation (SNL), the ability of dipeptide MrgC agonist JHU58 (0.1 mM, 10 μL, i.t.) to inhibit mechanical and heat hypersensitivity decreased after 3 days of treatment with a tolerance-inducing dose (0.5 mM, 10 μL, i.t., twice/day). ⋯ Furthermore, i.t. pretreatment with TAK-243, which reduced JHU58 tolerance, also attenuated the cross-tolerance to morphine analgesia. These findings suggest that tolerance can develop to MrgC agonist-induced pain inhibition after repeated i.t. administrations. This tolerance development to JHU58 may involve increased coupling of MrgC to β-arrestin-2 and ubiquitin-mediated receptor degradation.
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Intradermal administration of low-molecular-weight hyaluronan (LMWH) in the hind paw induced dose-dependent (0.1, 1, or 10 µg) mechanical hyperalgesia of similar magnitude in male and female rats. However, the duration of LMWH hyperalgesia was greater in females. This sexual dimorphism was eliminated by bilateral ovariectomy and by intrathecal administration of an oligodeoxynucleotide (ODN) antisense to the G-protein-coupled estrogen receptor (GPR30) mRNA in females, indicating estrogen dependence. ⋯ Low-molecular-weight hyaluronan-induced hyperalgesia was significantly attenuated by pretreatment with high-molecular-weight hyaluronan (HMWH) in male, but not in female rats. After gonadectomy or treatment with ODN antisense to GPR30 expression in females, HMWH produced similar attenuation of LMWH-induced hyperalgesia to that seen in males. These experiments identify nociceptors at which LMWH acts to produce mechanical hyperalgesia, establishes estrogen dependence in the role of RHAMM in female rats, and establishes estrogen dependence in the inhibition of LMWH-induced hyperalgesia by HMWH.
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The personalization of neuropathic pain treatment could be improved by identifying specific sensory phenotypes (ie, specific combinations of symptoms and signs) predictive of the response to different classes of drugs. A simple and reliable phenotyping method is required for such a strategy. We investigated the utility of an algorithm for stratifying patients into clusters corresponding to specific combinations of neuropathic symptoms assessed with the Neuropathic Pain Symptom Inventory (NPSI). ⋯ Each of the 97 patients with neuropathic pain included in these studies was individually allocated to one cluster, by applying the algorithm to their baseline NPSI responses. We found significant effects of botulinum toxin A relative to placebo in clusters 2 and 3, but not in cluster 1, suggesting that this approach was, indeed, relevant. Finally, we developed and performed a preliminary validation of a web-based version of the NPSI and algorithm for the stratification of patients in both research and daily practice.
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Codeine is one of the most commonly used opioid analgesics. Significant codeine-related morbidity and mortality prompted regulatory responses, with the up-scheduling of codeine combination analgesics to prescription-only medicines implemented in Australia in February 2018. This study investigated the impact of codeine up-scheduling on the number of codeine and other (noncodeine) prescription opioid-related emergency department (ED) presentations in a large metropolitan tertiary hospital. ⋯ Noncodeine prescription opioid-related (B = -1.90, P = 0.446) and ED presentations overall (B = -118.04, P = 0.140) remained unchanged immediately post-up-scheduling, with a significant change in trend from upward to downward for noncodeine (B = -0.76; P = 0.002) and ED presentations overall (B = -19.34, P = 0.022). A significant reduction of 4.58 (B = -4.58, P = 0.009) in codeine presentations involving subsequent hospital admission immediately post-up-scheduling was found; but no immediate reduction in codeine-related suicide-related overdoses, length of inpatient stay, or re-presentations (P > 0.0125; adjusted for multiple comparisons). Restricting supply of codeine to prescription-only may have resulted in less harmful codeine-related use in the community, without a corresponding immediate decrease in other opioid-related harms.
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In complex regional pain syndrome (CRPS), hyperalgesia encompasses uninjured sites on the ipsilateral side of the body and may also include the special senses because auditory discomfort often is greater on the CRPS-affected side. To determine whether this hemilateral hyperalgesia involves the visual system, the discomfort threshold to a light-source that increased in intensity at 100 lux/second from 500 to 3600 lux was investigated for each eye, and the nasal and temporal half of each visual field, in 33 patients with CRPS and 21 pain-free controls. Recent headache history was reviewed and, in patients with CRPS, sensitivity to mechanical and thermal stimuli was assessed in all 4 limbs and on each side of the forehead. ⋯ Similarly, mechanical and thermal hyperalgesia was greater in the CRPS-affected than contralateral limb and was greater ipsilateral than contralateral to CRPS in the forehead and nonsymptomatic limbs. Ipsilateral photophobia was associated with mechanical and thermal hyperalgesia in the ipsilateral forehead but not the CRPS-affected limb. Together, these findings suggest that aberrant processing of nociceptive input in the ipsilateral trigeminal-medullary region of the brainstem contributes to visual discomfort in CRPS.