The β2 adrenergic receptor regulates morphine tolerance and physical dependence

Abstract

Adaptations to the chronic administration of opioids reduce the utility of these drugs in treating pain and support addiction. Recent genetics-based approaches have implicated the β2 adrenergic receptor (β2-AR) in controlling some of these responses. We do not know, however, whether this receptor can modulate tolerance, dependence or changes in gene expression caused by chronic opioid administration. For our studies we used C57BL/6 mice and β2-AR knockout mice in the FVB background. Morphine dose response relationships were established both prior to and after chronic morphine treatment. In some cases, the selective β2-AR antagonist butoxamine was administered along with or after morphine. Physical dependence was assessed using naloxone-precipitated withdrawal. The expression of calcitonin gene related peptide (CGRP) and substance P (SP) were measured in spinal cord and dorsal root ganglion (DRG) tissues using both real-time PCR and enzyme-linked immunoassay (ELISA). Both the co-administration of butoxamine with morphine and the administration of butoxamine after chronic morphine reversed morphine tolerance. Morphine failed to cause tolerance in β2-AR knockout mice. Physical dependence was reduced under the same circumstances. The chronic administration of butoxamine with morphine reduced or eliminated the normally observed up-regulation of CGRP and SP in spinal cord and DRG tissues. Our results suggest that the β2-AR modulates both opioid tolerance and physical dependence. Activation of β2-ARs appears to be required for some of the key neurochemical changes which characterize chronic opioid administration. Therefore β2-AR antagonists show some promise as agents to enhance chronic opioid analgesic therapy.

Preprotachykinin-A Gene Disruption Attenuates Nociceptive Sensitivity After Opioid Administration and Incision by Peripheral and Spinal Mechanisms in Mice

“…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 .…”

“…Incision and nociceptive testing procedures began approximately 18 hours after the final dose of morphine or saline. This morphine administration protocol has been used extensively by the lab in studying opioid tolerance, dependence and hyperalgesia 42, 43, 45 . The selective NK-1 receptor antagonist LY303870 was obtained from Lilly Pharmaceuticals and prepared in sterile 0.9% saline and administered (30 mg/kg, i.p.)…”

Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

“…Following the results of a genetic study linking the b-adrenergic receptor to OIH [210], speculation arose regarding the clinical therapeutic effect of propranolol in treating OIH. Accordingly, Chu et al [47] conducted a clinical trial in which propranolol effectively eliminated secondary hyperalgesia in healthy volunteers receiving remifentanil infusion and undergoing experimental pain testing ( Table 3).…”

Beta-adrenergic antagonists during general anesthesia reduced postoperative pain: a systematic review and a meta-analysis of randomized controlled trials

“…Exposure to high doses of opioids during surgery may result in postoperative OIH and the spinal adrenergic beta-2 receptors may contribute to the neuroadaptive processes related to OIH [22]. In a recent study where electrical stimulation was used to generate areas of secondary mechanical hyperalgesia, remifentanil infusion increased the areas to 141 % of the baseline.…”