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Dear Editor We were pleased to learn about the observations of Wu et al. ⇓ related to the effect of ranolazine on doxorubicin-induced changes in the late sodium current that occur in dorsal root …

Objective The aim of this study was to determine whether ranolazine, a new medication that targets sodium channels to improve cardiac ischemia and angina, could be an effective analgesic agent for pain associated with demyelination injury. Background Many agents have been used to treat neuropathic pain but not all neuropathic conditions respond similarly to treatment. We have demonstrated that ranolazine, an agent that blocks voltage-gated sodium channels Nav 1.4, 1.5, 1.7, and 1.8, is effective in attenuating mechanical hyperalgesia in both complete Freund's adjuvant and spared nerve injury preclinical models of inflammatory and neuropathic pain, respectively. Here we test the efficacy of this drug in a newly validated model of demyelination injury that responds uniquely to a number of treatment options. Methods After determination of baseline nerve conduction velocities (NCVs) and withdrawal responses from heat and mechanical stimulation in male Sprague-Dawley rats (300–350 g), 1 μg/30 μL of doxorubicin was injected into one sciatic nerve. The contralateral nerve provided a sham-injected control. Two weeks after doxorubicin injection, NCV and sensitivity to heat and mechanical stimulation were reassessed before and after treatment with ranolazine (10, 30, 50 mg/kg) administered intraperitoneally using an experimenter-blinded, randomized design. Results Doxorubicin injection produced a significant hyperalgesic effect in response to mechanical but not heat stimulation. Conduction velocities in the injected limbs were reduced when compared with controls. Ranolazine reduced mechanical allodynia with peak efficacy at 30 mg/kg. Fifty milligram/kilogram ranolazine restored NCVs by approximately 50%, but had no effect in the uninjected limb. Conclusions Ranolazine exerts broad-spectrum actions to reduce mechanical allodynia that is associated with peripheral demyelination injury.

Objective. To compare the sensitivity of stimulating the plantar and dorsal hindpaw surfaces in the detection of mechanical allodynia and morphine analgesia. Background. Several approaches are used to assess nociceptive reactivity to mechanical stimulation in animal models of pain. Although certain techniques seem to be favored for studying specific nociceptive conditions, the differences between techniques have not been directly compared and characterized. We chose to compare methods employing stimulation applied to the dorsum of the paw with stimulation of the plantar surface to demonstrate the utility of each approach in determining baseline nociceptive thresholds, changes in those thresholds after injury, and analgesic efficacy. Methods. Withdrawal thresholds from mechanical stimulation applied to the dorsal and plantar surface of the hindpaw were measured in rats treated with morphine after receiving subcutaneous injections of complete Freund's adjuvant (CFA) using Semmes-Weinstein (S-W) monofilaments and electro von Frey (EVF) stimulation. Results. In contrast to stimulation of the dorsal surface, plantar hindpaw stimulation seldom elicited an aversive withdrawal response. Differences in withdrawal response from baseline were only detectible within the first 5 hours post-CFA and only with EVF stimulation. No significant differences in stimulation techniques were observed after the initial 5-hour window. Effective dose 50 (ED50) for analgesic efficacy was consistently lower using dorsal stimulation. Conclusions. Stimulation of the plantar surface of the paw is superior for detecting small changes in paw sensitivity at very low stimulus intensities, whereas stimulation of the dorsal surface is superior for delineating baseline pain thresholds and for detecting robust analgesia. Clinical Relevance. Reliable and sensitive assessment of animal pain behaviors is critical to translational pain research. This study demonstrates the importance of using proper test protocols in animal studies and its implication in preclinical screening of potential analgesics.

Objective. To determine the effect of streptozotocin (STZ)-induced diabetes on the development and recovery of thermal and mechanical hyperalgesia associated with inflammation induced by subcutaneous injection of complete Freund's adjuvant (CFA). Background. The response to nociceptive injury in diabetes differs from that seen in normal individuals in that diabetic patients have increased susceptibility to infections and recover slowly or incompletely from infections and tissue injury due to an abnormal inflammatory response. We have chosen to examine the effect of STZ-induced hypoinsulinemia on the hyperalgesia associated with the enhanced inflammatory state that is induced by the subcutaneous injection of CFA to delineate the potential role of insulin in the development of chronic pain. Methods. STZ- and vehicle-treated Sprague-Dawley rats were tested using thermal and mechanical stimulation after subcutaneous injection of CFA. The behavioral response was compared with that similarly determined in non-diabetic controls and insulin-depleted rats that received insulin replacement. Results. Recovery of the thermal hyperalgesic response to baseline levels occurred over a period of 9–14 days, but the allodynic response to mechanical stimulation persisted for the duration of the study in STZ-treated rats. Insulin replacement prevented the delay in recovery of mechanical allodynia, but had no obvious effect on nociception in uninflamed tissue. Conclusions. Normal insulin function is essential for recovery from mechanical allodynia associated with inflammation induced by CFA. Altered insulin metabolism may selectively influence fiber-type specific mechanisms related to mechanical allodynia associated with inflammation and wound healing.

Objective. To determine whether ranolazine, a newanti-angina medication, could be an effective anal-gesic agent in complete Freund’s adjuvant-inducedinflammatory pain.Background. Plantar injection of complete Freund’sadjuvant (CFA) produces an extended period ofhyperalgesia that is associated with a dramaticup-regulation of Na v 1.7 sodium channels in popula-tions of large and small dorsal root ganglionneurons related to the injection site. Ranolazineappears to produce its anti-angina effect throughblocking the late sodium current associated with thevoltage-gated sodium channel, Na v 1.5. Becauseranolazine also inhibits Na v 1.7, and 1.8, we soughtto determine whether it could be an effective anal-gesic agent in CFA-induced inflammatory pain.Methods. Baseline determinations of withdrawalfrom thermal and mechanical stimulation were madein Sprague-Dawley rats ( ~ 300–350 ¥ g ). Followingdetermination of baseline, one hindpaw in eachgroup was injected with 0.1 mL of CFA. The con-tralateral paw received saline. Thermal andmechanical stimulation was repeated on the thirdday post-injection. Vehicle (0.9% isotonic saline;pH 3.0) or ranolazine was then administered in ran-domized and blinded doses either by intraperitoneal(ip) injection (0, 10, 20, and 50 mg/kg) or by oralgavage (po; 0, 20, 50, 100, and 200 mg/kg). Animalswere again tested 30 minutes (ip) and 1 hour (po)after drug administration.Results. Ranolazine produced dose-dependantanalgesia on mechanical allodynia induced by CFAinjection, but had no effect on thermal hyperalgesia.Conclusions. Ranolazine’s potential as a newoption for managing both angina and chronicinflammatory pain warrants further study.Key Words. Ranolazine; CFA; Pain; AllodyniaIntroduction