Once used most commonly for the management of cancer related pain and pain due to acute trauma, opioids have increased in popularity for controlling chronic non-malignant pain over the past decade 47
. Though the efficacy and risks of using these drugs for more common forms of chronic pain remain somewhat controversial, it is natural that an increasing percentage of patients having surgical procedures will have histories of previous opioid use. Unfortunately, opioid-induced hyperalgesia (OIH) may both limit the efficacy of opioid use, and pose challenges for the management of these patients postoperatively 3, 13, 38, 59
. Indeed, various studies demonstrate that chronic opioid use portends greater postoperative pain, and possibly a greater likelihood of experiencing opioid-related side effects 25, 46, 51, 54
. To date few studies have systematically evaluated methods for preventing or controlling postoperative pain in this population. On the other hand, several putative mechanisms supporting OIH are currently or soon will be amenable to modulation with clinically available medications. One such mechanism felt from preclinical studies to support OIH is NK1 receptor activation by the ppt-A
gene product substance P (SP) 33, 61
In these studies we sought to better establish the role SP-NK1 signaling might have in supporting OIH as it interacts with incision-related sensitization. The principal findings of our studies were, 1) that mice repeatedly treated with opioids show prolonged recovery times from mechanical sensitization after hindpaw incision, 2) that both incision and morphine treatment up-regulate ppt-A in DRG tissue, 3) that while incision and repeated morphine treatment elevate the levels of several pro-nociceptive cytokines, SP-NK1 signaling appears to have little influence on those increases, 4) that NGF is very strongly up-regulated in incised tissue if the animals are pretreated with morphine, and SP-NK1 signaling is critical for this effect, and 5) that the up-regulation of several other genes for which there exists substantial evidence of participation in OIH is dependent upon SP-NK1 signaling ().
Table 1 Summary of expression changes in skin, DRG and spinal cord tissue after treatment with morphine, hindpaw incision or both. Cells are designated “+” if a statistically significant difference was found versus control at the p≤0.05 (more ...)
The choice of the SP-NK1 system for study was supported by evidence linking this system to opioid adaptations such as tolerance and OIH in spinal cord and DRG tissues. Studies have shown an increased synthesis of SP in cultured DRG neurons, and our own data show an up-regulation of pre-protachykinin mRNA in DRG tissue from morphine treated mice 6, 44, 45
. The spinal cord content of SP, present mostly in the terminals of afferent nerve fibers is increased in morphine treated mice 45
. Additional studies have shown that the release of this neurotransmitter in response to noxious stimulation is augmented in animals undergoing sustained morphine treatment using the rate of internalization of post-synaptic NK1 receptors as an assay 33
. Ablation of spinal NK1 expressing cells reduces analgesic tolerance to spinally administered morphine 61
. More importantly, the use of an intrathecally delivered NK1 antagonist was observed to block OIH assessed by momentary thermal stimuli 33
. Prior to this time the role of SP-NK1 signaling and opioid exposure in a model of clinically relevant incisional pain had not been undertaken. Indeed, we observed ppt-A
null mutant mice or WT mice treated with a selective NK1 antagonist to display reduced development of OIH after repeated morphine treatment, and the exacerbation of mechanical sensitization after incision in similarly pretreated animals was also reduced. It was demonstrated recently that SP-NK1 signaling controls mechanical sensitization after incision perhaps making it reasonable to hypothesize that opioid treatment might further exacerbate sensitization 57
Though most investigations involving OIH have focused on CNS tissues, more peripheral mechanisms should not be discounted as potentially contributing. This is particularly true in models involving tissue inflammation and trauma as various peripheral tissues such as components of skin express opioid receptors as well as receptors for neurotransmitters such as SP produced in overabundance in opioid treated animals 8, 11, 36
. Likewise, sensory neurons express opioid receptors on their peripheral terminals 9
. In fact, early studies demonstrated that very low doses of opioid receptor antagonists administered into the skin of opioid treated rats could cause hyperalgesia 1
. Several studies have demonstrated effects of opioids on wound healing suggesting functionally relevant peripheral sites of action 7, 10
. Our laboratory has examined the levels of nociception-related cytokines after incision in control and morphine treated mice and have found the levels of some of these mediators to be moderately increased in mice repeatedly treated with morphine, consistent the greater sensitization observed 17, 57
. In the present studies we chose to analyze opioid and SP-NK1 effects on the levels of IL-1β, IL-6, MIP-1α and G-CSF because each of these is elevated in peri-incisional skin and each can contribute to nociceptive sensitization. For IL-1β, IL-6, MIP-1α and G-CSF we observed morphine to further enhance the peri-incisional levels yet deletion of the ppt-A
gene had no discernable effect. Thus the opioid-induced exacerbation of mechanical sensitization after incision does not appear to depend upon opioid-induced enhancement of the levels of several key cytokines.
On the other hand, we found robust effects for both morphine treatment and SP-NK1 signaling on peri-incisional NGF levels. The neurotrophin NGF is of particular interest because of its strong association with incisional pain. Several studies report the expression of NGF after incision, particularly in keratinocytes and peri-incisional fibroblasts 4, 63
. In mice pretreated with morphine for 4 days, basal skin levels of NGF were not changed. However, morphine pretreated mice with incisions demonstrated approximately 10-fold increases in NGF and these changes were demonstrated to depend on SP-NK1 signaling, as ppt-A
gene deletion or blocking the NK1 receptor greatly reduced augmented NGF levels. Thus the over-expression of NGF after incision in mice treated repeatedly with morphine may play a role in their prolonged sensitization after incision, though there is little evidence that changes in peripheral NGF levels participate in the sensitization to transient noxious stimuli applied to intact skin.
Alterations in gene expression in spinal cord and DRG tissues have been studied in relation to OIH and incision. We hypothesized that the expression of genes whose products have well demonstrated roles in supporting OIH would be increased by morphine treatment alone and further augmented within 24 hours of incision. We also hypothesized that these changes would be dependent on SP-NK1 signaling. Indeed morphine treatment enhanced the expression of genes coding for prodynorphin, NMDAR1 and NK1 (spinal cord)34, 41
, and the 5-HT3 receptor as well as mRNA of the SP precursor itself in the DRG 16, 44, 45
. In all cases the combination of incision plus morphine treatment leads to higher levels of expression than incision alone. The effects of incision, morphine treatment and their combination were eliminated in ppt-A
null mutant mice. These observations suggest that SP-NK1 signaling is a mechanism on which incision and chronic morphine treatment converge to regulate the expression of genes which in turn support nociceptive sensitization.
Pain after surgery remains an unresolved yet common clinical problem. Unfortunately, the management of postoperative pain in opioid consuming patients is even more problematic, and the number of patients in this situation is likely to grow. Understanding mechanisms supporting pain in the setting of tissue trauma and opioid exposure may lead to strategies reducing excess pain. While very little work has been done to identify effective treatment approaches in this setting, one recent study demonstrated that use of the NMDA receptor blocker ketamine could reduce postoperative opioid requirements in previously opioid exposed patients undergoing spine surgery 46
. The analogous laboratory model employed in the present study provides a potential role for spinal cord NMDA receptors in augmented hyperalgesia seen after incision in previously opioid exposed mice, consistent with the results of the ketamine trial. In addition, potent NK1 receptor antagonists are now available and possibly would have special value as adjuvant in opioid consuming populations undergoing surgery. Likewise, 5-HT3 antagonists are commonly used as antiemetics though analgesic properties have not emerged in their two decades of clinical use. Perhaps in the setting of incision and chronic opioid use, these 5-HT3 antagonists might become a more useful analgesic target. Lastly, biologic anti-NGF antibodies are being developed as analgesics, and appear to have a broad spectrum of action in pre-clinical studies 4, 30, 50, 56, 63
. The observed link between sustained morphine exposure and enhance peripheral NGF production suggests that these anti-NGF agents may be particularly useful in treating pain in the post-surgical chronic opioid consuming patient. In any case, our observations add to the growing body of evidence that both peripheral and central mechanisms may contribute to the high pain levels experienced by opioid consuming patients after surgery.