Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

Abstract

Opioids are frequently used for the treatment of pain following spinal cord injury (SCI). Unfortunately, we have shown that morphine administered in the acute phase of SCI results in significant, adverse secondary consequences including compromised locomotor and sensory recovery. Similarly, we showed that selective activation of the j-opioid receptor (KOR), even at a dose 32-fold lower than morphine, is sufficient to attenuate recovery of locomotor function. In the current study, we tested whether activation of the KOR is necessary to produce morphine's adverse effects using norBinaltorphimine (norBNI), a selective KOR antagonist. Rats received a moderate spinal contusion (T12) and 24 h later, baseline locomotor function and nociceptive reactivity were assessed. Rats were then administered norBNI (0, 0.02, 0.08, or 0.32 lmol) followed by morphine (0 or 0.32 lmol). Nociception was reassessed 30 min after drug treatment, and recovery was evaluated for 21 days. The effects of norBNI on morphine-induced attenuation of recovery were dose dependent. At higher doses, norBNI blocked the adverse effects of morphine on locomotor recovery, but analgesia was also significantly decreased. Conversely, at low doses, analgesia was maintained, but the adverse effects on recovery persisted. A moderate dose of norBNI, however, adequately protected against morphine's adverse effects without eliminating its analgesic efficacy. This suggests that activation of the KOR system plays a significant role in the morphineinduced attenuation of recovery. Our research suggests that morphine, and other opioid analgesics, may be contraindicated for the SCI population. Blocking KOR activity may be a viable strategy for improving the safety of clinical opioid use.

Opioid Analgesia and Opioid-Induced Adverse Effects: A Review

“…However, the behavioural changes in response to chronic morphine treatment are independent of MOP receptor, cyclin-dependent kinase 5 (cdk5) or adenylyl cyclase activities in relevant areas of the brain [216]. Studies suggested that the morphine-induced behavioural effects are probably derived from its binding to the KOP receptor but not to the MOP receptor [217,218]. The likely multiple mechanisms that link chronic morphine treatment to its behavioural effects are not completely understood but may be controlled by a combination of dopaminergic, GABAergic, opioidergic and additional unknown neuronal signals [107,[202][203][204][212][213][214].…”

Morphine-induced changes in the function of microglia and macrophages after spinal cord injury

“…Not surprisingly, there was a main effect of surgery on CD86 expressing macrophages, with contused rats exhibiting signi cantly higher numbers of CD86+ macrophages than shams on Day 7 post injury (F (1, 20) = 16.07, p < 0.001, Figure 7C). Additionally, we previously found that activation of KORs is both su cient and necessary to mediate the negative effects of morphine on motor recovery in the rat model of SCI [12,13]. To explore whether morphine administration altered the expression of opioid receptors on speci c subpopulations of immune cells we quanti ed KOR expression within the CD86+ subpopulations of microglia and macrophages.…”

“…Our data from a rat SCI model suggests that opioid administration causes acute and long-term pain, rather than a correlative association with higher pain leading to greater opioid use. In the rat model, our laboratory has repeatedly found that morphine given in the days following the injury signi cantly undermines locomotor function, increases cell death around the lesion, and increases chronic pain [7][8][9][10][11][12][13][14][15]. Given the limited number of effective analgesics, it is critical that we develop a better understanding of the molecular consequences of activating opioid receptors within the highly in ammatory context of SCI.…”

“…Following the contusion (or sham) surgery, body weight was recorded daily. Rats that received the contusion surgery also lost bladder function, and they were manually expressed daily in the morning (7:00-9:30) and evening (16:30-18:00) until an empty bladder was observed for 3 consecutive days[8, 12,13]. Rats were maintained on a 12-h light/dark cycle, with behavioral testing conducted during the light cycle.…”

Nanofiber Scaffolds as Drug Delivery Systems to Bridge Spinal Cord Injury

“…In the last two years, many research studies, focusing on the identification of drugs potentially effective in SCI treatment, have been published [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ,…”