Sustained Morphine Exposure Induces a Spinal Dynorphin-Dependent Enhancement of Excitatory Transmitter Release from Primary Afferent Fibers

Abstract

Paradoxical opioid-induced pain has been demonstrated repeatedly in humans and animals. The mechanisms of such pain are unknown but may relate to opioid-induced activation of descending pain facilitatory systems and enhanced expression and pronociceptive actions of spinal dynorphin. Here, the possibility that these opioid-induced central changes might mediate increased excitability to the spinal cord was tested. Tactile and thermal hypersensitivity was observed at 7, but not 1, days after subcutaneous morphine pellet implantation; placebo pellets produced no effects. Basal and capsaicin-evoked release of calcitonin gene-related peptide (CGRP) was measured in minced spinal tissues taken from naive rats or rats on post-pellet days 1 and 7. The content and evoked release of CGRP were significantly increased in tissues from morphine-exposed rats at 7, but not 1, days after implantation. Morphine increased spinal dynorphin content on day 7 in rats with sham bilateral lesions of the dorsolateral funiculus (DLF) but not in rats with DLF lesions. Pharmacological application of dynorphin A(2-13), a non-opioid fragment, to tissues from naive rats enhanced the evoked release of CGRP. Enhanced evoked release of CGRP from morphine-pelleted rats was blocked by dynorphin antiserum or by previous lesions of the DLF. Sustained morphine induces plasticity in both primary afferents and spinal cord, including increased CGRP and dynorphin content. Morphine-induced elevation of spinal dynorphin content depends on descending influences and enhances stimulated CGRP release. Enhanced transmitter release may allow increased stimulus-evoked spinal excitation, which is likely to be critical for opioid-induced paradoxical pain. Such pain may manifest behaviorally as antinociceptive tolerance.

Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner

“…Thus, sustained morphine treatment was shown to enhance the content and release of excitatory neurotransmitters, including the pronociceptive neurotransmitter CGRP in the dorsal horn of the spinal cord (Menard 1995a(Menard , 1995bMa et al 2000;Gardell et al 2002;Trang et al 2005). Indeed, supporting the above observation, in the present work we demonstrate that 24 h morphine treatment significantly augments basal CGRP release from cultured neonatal rat primary sensory neurons (141% of control).…”

Peripheral cannabinoids attenuate carcinoma-induced nociception in mice

“…[25,26,33] Cannabinoids are analgesic in patients with neuropathic pain [12,13,20,24,34] and show promise in cancer pain. [32] Cannabinoids activate two receptors types: cannabinoid receptor 1 and 2 (CBr1 and CBr2, respectively).…”

Role of NK-1 neurotransmission in opioid-induced hyperalgesia

“…Opioid-induced 'pain', i.e. hyperalgesia, has been reliably observed in preclinical models (Celerier et al, 2000;Gardell et al, 2002;Larcher et al, 1998;Mao et al, 1994;Vanderah et al, 2000Vanderah et al, , 2001aYaksh and Harty, 1988;Yaksh et al, 1986). Recent research has begun to uncover the neurobiological consequences of sustained opioid administration and reveal several neuroplastic adaptations that likely underlie opioid-induced hyperalgesia (Gardell et al, 2002;Ma et al, 2000;Vanderah et al, 2000Vanderah et al, , 2001a.…”