TY - JOUR
T1 - Suppression of active phase voluntary wheel running in male rats by unilateral chronic constriction injury
T2 - Enduring therapeutic effects of a brief treatment of morphine combined with TLR4 or P2X7 antagonists
AU - Green-Fulgham, Suzanne M.
AU - Ball, Jayson B.
AU - Maier, Steven F.
AU - Rice, Kenner C.
AU - Watkins, Linda R.
AU - Grace, Peter M.
N1 - Funding Information:
Supported by Department of Defense grant W81XWH-16-1-0161 (L.R.W.), NIH R01 DA044934 (L.R.W.), University of Texas Rising STARs Award (P.M.G.), and by the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse Intramural Research Programs. Morphine was gifted from the National Institute on Drug Abuse Drug Supply Program (NDSP) Division of Therapeutics and Medical Consequences, Research Triangle Institute, NC. The Toll-like receptor 4 (TLR4) antagonist (+)-Naloxone was synthesized by Dr. Kenner Rice (National Institute on Drug Abuse/National Institute on Alcohol Abuse and Alcoholism, Bethesda) for use in these studies. Supported by Department of Defense grant W81XWH-16-1-0161 (L.R.W.), NIH R01 DA044934 (L.R.W.), University of Texas Rising STARs Award (P.M.G.)., and by the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse Intramural Research Programs.
Funding Information:
Supported by Department of Defense grant W81XWH‐16‐1‐0161 (L.R.W.), NIH R01 DA044934 (L.R.W.), University of Texas Rising STARs Award (P.M.G.), and by the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse Intramural Research Programs.
Funding Information:
Morphine was gifted from the National Institute on Drug Abuse Drug Supply Program (NDSP) Division of Therapeutics and Medical Consequences, Research Triangle Institute, NC. The Toll‐like receptor 4 (TLR4) antagonist (+)‐Naloxone was synthesized by Dr. Kenner Rice (National Institute on Drug Abuse/National Institute on Alcohol Abuse and Alcoholism, Bethesda) for use in these studies. Supported by Department of Defense grant W81XWH‐16‐1‐0161 (L.R.W.), NIH R01 DA044934 (L.R.W.), University of Texas Rising STARs Award (P.M.G.)., and by the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse Intramural Research Programs.
Publisher Copyright:
© 2020 Wiley Periodicals LLC
PY - 2022/1
Y1 - 2022/1
N2 - The present series of studies examine the impact of systemically administered therapeutics on peripheral nerve injury (males; unilateral sciatic chronic constriction injury [CCI])-induced suppression of voluntary wheel running, across weeks after dosing cessation. Following CCI, active phase running distance and speed are suppressed throughout the 7-week observation period. A brief course of morphine, however, increased active phase running distance and speed throughout this same period, an effect apparent only in sham rats. For CCI rats, systemic co-administration of morphine with antagonists of either P2X7 (A438079) or TLR4 ((+)-naloxone) (receptors critical to the activation of NLRP3 inflammasomes and consequent inflammatory cascades) returned running behavior of CCI rats to that of shams through 5+ weeks after dosing ceased. This is a striking difference in effect compared to our prior CCI allodynia results using systemic morphine plus intrathecal delivery of these same antagonists, wherein a sustained albeit partial suppression of neuropathic pain was observed. This may point to actions of the systemic drugs at multiple sites along the neuraxis, modulating injury-induced, inflammasome-mediated effects at the injured sciatic nerve and/or dorsal root ganglia, spinal cord, and potentially higher levels. Given that our data to date point to morphine amplifying neuroinflammatory processes put into motion by nerve injury, it is intriguing to speculate that co-administration of TLR4 and/or P2X7 antagonists can intervene in these inflammatory processes in a beneficial way. That is, that systemic administration of such compounds may suppress inflammatory damage at multiple sites, rapidly and persistently returning neuropathic animals to sham levels of response.
AB - The present series of studies examine the impact of systemically administered therapeutics on peripheral nerve injury (males; unilateral sciatic chronic constriction injury [CCI])-induced suppression of voluntary wheel running, across weeks after dosing cessation. Following CCI, active phase running distance and speed are suppressed throughout the 7-week observation period. A brief course of morphine, however, increased active phase running distance and speed throughout this same period, an effect apparent only in sham rats. For CCI rats, systemic co-administration of morphine with antagonists of either P2X7 (A438079) or TLR4 ((+)-naloxone) (receptors critical to the activation of NLRP3 inflammasomes and consequent inflammatory cascades) returned running behavior of CCI rats to that of shams through 5+ weeks after dosing ceased. This is a striking difference in effect compared to our prior CCI allodynia results using systemic morphine plus intrathecal delivery of these same antagonists, wherein a sustained albeit partial suppression of neuropathic pain was observed. This may point to actions of the systemic drugs at multiple sites along the neuraxis, modulating injury-induced, inflammasome-mediated effects at the injured sciatic nerve and/or dorsal root ganglia, spinal cord, and potentially higher levels. Given that our data to date point to morphine amplifying neuroinflammatory processes put into motion by nerve injury, it is intriguing to speculate that co-administration of TLR4 and/or P2X7 antagonists can intervene in these inflammatory processes in a beneficial way. That is, that systemic administration of such compounds may suppress inflammatory damage at multiple sites, rapidly and persistently returning neuropathic animals to sham levels of response.
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U2 - 10.1002/jnr.24645
DO - 10.1002/jnr.24645
M3 - Article
C2 - 32533604
AN - SCOPUS:85086338895
SN - 0360-4012
VL - 100
SP - 265
EP - 277
JO - Journal of neuroscience research
JF - Journal of neuroscience research
IS - 1
ER -