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Objectives Pain is the hallmark symptom of sickle cell disease (SCD), yet the types of pain that these patients experience, and the underlying mechanisms, have not been well characterized. The study purpose was to determine the safety and utility of a mechanical and thermal quantitative sensory testing (QST) protocol and the feasibility of utilizing neuropathic pain questionnaires among adults with SCD. Methods A convenience sample (N=25, 18 women, mean age 38.5 ± 12.5 [20–58 years]) completed self-report pain and quality-of-life tools. Subjects also underwent testing with the TSA-II NeuroSensory Analyzer and calibrated von Frey microfilaments. Results We found that the QST protocol was safe and did not stimulate a SCD pain crisis. There was evidence of central sensitization (n=15), peripheral sensitization (n=1), a mix of central and peripheral sensitization (n=8), or no sensitization (n=1). The neuropathic pain self-report tools were feasible with evidence of construct validity; 40% of the subjects reported S-LANSS scores that were indicative of neuropathic pain and had evidence of central, peripheral or mixed sensitization. Discussion The QST protocol can be safely conducted in adults with SCD and provides evidence of central or peripheral sensitization, which is consistent with a neuropathic component to SCD pain. These findings are novel, warrant a larger confirmatory study, and indicate the need for normative QST data from African American adults and older adults.

Ca2ϩ /calmodulin-dependent protein kinase II (CaMKII) is a major protein kinase that is capable of regulating the activities of many ion channels and receptors. In the present study, the role of CaMKII in the complete Freund's adjuvant (CFA)-induced inflammatory pain was investigated. Intraplantarly injected CFA was found to induce spinal activity of CaMKII (phosphorylated CaMKII), which was blocked by KN93 [[2-[N-(2-hydroxyethyl) ]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-Nmethylbenzylamine)], a CaMKII inhibitor. Pretreatment with KN93(i.t.) dose-dependently prevented the development of CFAinduced thermal hyperalgesia and mechanical allodynia. Acute treatment with KN93 (i.t.) also dose-dependently reversed CFAinduced thermal hyperalgesia and mechanical allodynia. The action of KN93 started in 30 min and lasted for at least 2 to 4 h.

Repeated administration of opioids not only leads to tolerance and dependence, but also results in nociceptive enhancement called opioid-induced hyperalgesia (OIH). Nociceptive mediators involved in OIH generation remain poorly understood. In the present study, we tested the hypothesis that Ca 2ϩ /calmodulin-depent protein kinase II (CaMKII␣) is critical for OIH. Opioid-induced hyperalgesia was produced by repeated morphine administration or pellet implantation in mice. Correlating with the development of tactile allodynia and thermal hyperalgesia, spinal CaMKII␣ activity was significantly increased in OIH. KN93, a CaMKII inhibitor, dose-and time-dependently reversed OIH and CaMKII activation without impairing locomotor coordination. To elucidate the specific CaMKII isoform involved, we targeted CaMKII␣ by using small interfering RNA and demonstrated that knockdown of spinal CaMKII␣ attenuated OIH. Furthermore, morphine failed to induce OIH in CaMKII␣ T286A point mutant mice, although wild-type littermate mice developed robust OIH after repeated treatments with morphine. These data implicate, for the first time, an essential role of CaMKII␣ as a cellular mechanism leading to and maintaining opioid-induced hyperalgesia.

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