Morphine-induced allodynia and trigeminal neuroplasticity: possible relevance to medication overuse headache

Milena De Felice, Juliana Chichorro, Ruizhong Wang, Todd W. Vanderah, Michael H. Ossipov, Frank Porreca. University of Arizona, United States.

Medications used in the treatment of headache, including triptans and opiates, have been linked to the phenomenon of medication overuse headache (MOH). The mechanisms by which medications may increase the frequency of headache are not known. Here, possible neural adaptations elicited by sustained morphine exposure and potential alterations in responses to proposed “triggers” of headache were explored. Male, S.D. rats received morphine (7.7 mg/kg day, s.c.) across 6 days through osmotic mini-pumps. Sensory thresholds were measured by determining the behavioral response to probing the para-ocular region of the face and the hindpaw with calibrated von Frey filaments. Sustained morphine exposure resulted in a time-dependent emergence of tactile hypersensitivity of both the facial region and the hindpaws. Allodynia was first observed 3 days after sustained morphine exposure and was expressed throughout the infusion period (day 6); thresholds returned to baseline levels by approximately day 18. Morphine-induced allodynia was reversed by acute treatment with sumatriptan or naproxen. Sustained morphine enhanced CGRP content and capsaicin-evoked CGRP release in the nucleus caudalis. Enhanced capsaicin-evoked CGRP release was blocked by sumatriptan or naproxen. Sustained morphine resulted in upregulation of CGRP in identified dural afferents and increased expression was observed in IB4 (i.e., “peptide-poor”) and NF200 positive cells. Morphine failed to induce upregulation of SP in identified dural afferents. Critically, the expression of CGRP was still elevated 14 days after termination of morphine infusion, a time-point at which morphine-induced allodynia had resolved. On day 20 when sensory thresholds were at pre-drug baseline levels, morphine or saline pre-exposed rats received systemic sodium nitroprusside (an NO donor) or a 1 hr period of stress (i.e., unrestrained exposure to a bright light). Both, the NO donor or stress, re-instated facial and hindpaw allodynia in morphine-, but not saline-, pretreated rats. These observations suggest that exposure to morphine over a period of days results in long-lasting neuroadaptive changes that promote a state of increased responsiveness, and susceptibility to stimuli that may promote activation of the nociceptive trigeminal system.