Jennifer A. Shumilla

The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain

Controlling neuropathic pain is an unmet medical need and we set out to identify new therapeutic candidates. AV411 (ibudilast) is a relatively nonselective phosphodiesterase inhibitor that also suppresses glial-cell activation and can partition into the CNS. Recent data strongly implicate activated glial cells in the spinal cord in the development and maintenance of neuropathic pain. We hypothesized that AV411 might be effective in the treatment of neuropathic pain and, hence, tested whether it attenuates the mechanical allodynia induced in rats by chronic constriction injury (CCI) of the sciatic nerve, spinal nerve ligation (SNL) and the chemotherapeutic paclitaxel (Taxol). Twice-daily systemic administration of AV411 for multiple days resulted in a sustained attenuation of CCI-induced allodynia. Reversal of allodynia was of similar magnitude to that observed with gabapentin and enhanced efficacy was observed in combination. We further show that multi-day AV411 reduces SNL-induced allodynia, and reverses and prevents paclitaxel-induced allodynia. Also, AV411 cotreatment attenuates tolerance to morphine in nerve-injured rats. Safety pharmacology, pharmacokinetic and initial mechanistic analyses were also performed. Overall, the results indicate that AV411 is effective in diverse models of neuropathic pain and support further exploration of its potential as a therapeutic agent for the treatment of neuropathic pain.

Antinociceptive action of a p38α MAPK inhibitor, SD-282, in a diabetic neuropathy model

&NA; Diabetes can induce a bewildering list of sensory changes, including alteration in pain sensitivity. Painful diabetic neuropathy is refractory to most common analgesics. This study examined the effect of a p38&agr; MAPK inhibitor, SD‐282, on mechanical allodynia, thermal hyperalgesia, and formalin‐evoked nociception in streptozotocin‐induced diabetic rats. Four‐week diabetic rats exhibited mechanical allodynia, decreased mechanical thresholds, and C‐ and A&dgr;‐fiber mediated thermal hyperalgesia. Mechanical and thermal responses were measured in diabetic rats following acute and repeated intraperitoneal administration of vehicle, 15 or 45 mg/kg SD‐282. Mechanical allodynia was reversed by acute and repeated administration of 15 and 45 mg/kg SD‐282. Repeated administration of 15 or 45 mg/kg SD‐282 prevented the exacerbation of C‐, but not A&dgr;‐fiber, mediated thermal hyperalgesia. Repeated administration of 45 mg/kg SD‐282 attenuated flinching behaviors during the quiescent period and the second phase of the formalin response in diabetic rats. Acute and repeated administration of 15 or 45 mg/kg SD‐282 had no effect on mechanical, thermal or formalin responses in age‐matched control rats. These results indicate a potential therapeutic value of p38&agr; MAPK inhibitors in the treatment of aberrant pain sensitivity produced by diabetes.

Acute and chronic ethanol exacerbates formalin pain in neonatal rats

We have previously reported that withdrawal from acute ethanol (EtOH) exposure lowers mechanical thresholds in post-natal day 7 (P7) and post-natal day 21 (P21) rats. The present study tested the hypothesis that daily administration of 4 g/kg 15% EtOH for 5 days in rats during the human developmental equivalent of the third trimester, but not at a later time in development, would alter mechanical thresholds and formalin-induced pain behaviors. A transient decrease in mechanical thresholds (allodynia) was observed in P7 rats upon withdrawal from repeated EtOH between P3 and P7. When challenged with intraplantar formalin on P11, rats exposed to acute or chronic EtOH had enhanced phase II pain behaviors. In contrast to chronic EtOH administration to rats between P3 and P7, prolonged mechanical allodynia was observed in P21 rats upon withdrawal from chronic EtOH between P17 and P21. Formalin responses were unchanged in P25 rats exposed to acute or chronic EtOH. The affects of EtOH on somatosensory processing are dependent upon the age at which exposure occurs.

Systemic administration of propentofylline does not attenuate morphine tolerance in non-injured rodents

Propentofylline is a phosphodiesterase inhibitor that has been shown to attenuate the onset of morphine tolerance when administered intrathecally to rats. The present studies examined whether systemic administration could be effective in attenuating morphine tolerance in non-injured rodents using a similar dosing paradigm. Propentofylline at 10, 30, or 50 mg/kg, administered intraperitoneally once daily for 5 days, was unable to attenuate morphine tolerance established by twice daily administration of 10 mg/kg morphine. These results suggest that direct delivery of propentofylline to the central nervous system (CNS) may be required in order to attenuate morphine tolerance.

Acute and chronic ethanol does not affect incisional pain in neonatal rats

We have previously found that in post-natal day 7 rats withdrawal from acute and chronic ethanol (EtOH) exposure lowers mechanical thresholds during withdrawal and exacerbates spontaneous pain responses to an inflammatory injury 4 days post-withdrawal. These findings suggested alterations in somatosensory pathways following EtOH exposure during the third trimester developmental equivalent. In this study we wanted to determine whether EtOH exposure during the third trimester equivalent exacerbates mechanical allodynia and thermal hyperalgesia produced by an incisional model of post-operative pain at post-natal day 21. The extent and duration of mechanical allodynia and thermal hyperalgesia following incision was measured and found to be unaffected by prior EtOH exposure.

Protein kinase c ϵ and γ: roles in age-specific modulation of acute opioid-withdrawal allodynia

Abstract Acute morphine withdrawal results in enhanced responsiveness to noxious stimulation in adult humans and rodents. This study extends these findings by demonstrating that acute morphine withdrawal produces allodynia in neonatal rats that is dependent on the translocation of protein kinase C ϵ and γ (ϵPKC and γPKC, respectively) in a developmentally specific manner. Basal expression of ϵPKC in dorsal root ganglia, and γPKC in lamina II of the lumbar spinal cord, were lower in postnatal day 7 (P7) compared with P21 rats. ϵPKC immunoreactivity increased in P7 rats at 4 hours after acute administration of morphine, whereas ϵPKC immunoreactivity decreased at 4 hours in P21 rats. In contrast to ϵPKC, there was a loss of γPKC immunoreactivity following morphine administration in both P7 and P21 rats. To determine whether ϵ and γPKC contribute to acute withdrawal-induced allodynia in neonatal rats, isozyme-specific inhibitors of ϵ and γPKC translocation were administered before or after morphine administration. Naloxone was used to precipitate withdrawal at either 30 or 120 minutes after morphine, or animals were allowed to undergo natural withdrawal from a single dose of morphine. Inhibition of ϵ but not γPKC prevented naloxone-precipitated allodynia 30 minutes after morphine administration in P7 rats. In contrast, both ϵ and γPKC inhibitors attenuated naloxone-precipitated allodynia in P21 rats. Allodynia was attenuated in P7 and P21 rats by administration of either ϵ or γPKC inhibitor when withdrawal was precipitated at 2 hours after morphine or animals underwent natural withdrawal. This work demonstrates that the role of ϵ and γPKC in acute withdrawal-induced allodynia is developmentally regulated in a temporally specific manner.