Chronic but Not Acute Exposure to Morphine Enhances nAChR Mediated Responses in Enteric Neurons

A major side‐effect of chronic opioid treatment is constipation whereas withdrawal following chronic exposure leads to diarrhea and increased GI motility. Previous studies have shown that chronic opioids enhance sensitivity to nicotine in the GI tract. In this study we examined the sensitivity to nicotine following short (10 mins) and long‐term exposure (16‐20 h) to morphine in isolated mouse single enteric neurons using patch‐clamp technique. Nicotine induced inward currents from holding potential of ‐60 mV in a dose‐dependent manner. The amplitude of the nicotine induced currents were significantly increased in neurons exposed for long‐term (16‐20h) but not short‐term (10 mins) to morphine (3 μM). The maximal current densities induced by 1mM nicotine were 139 ± 40 pA/pF, 135 ± 31 pA/pF and 274 ± 29 pA/pF (p<0.05) in control, short‐term and long‐term morphine treated cells respectively. We have previously shown that tolerance and dependence to chronic morphine occurs in the ileum but not the colon. To test if the enhanced nicotine responses are dependent on morphine tolerance and dependence, nicotine responses were determined in colonic enteric neurons. The maximal current densities induced by 1mM nicotine were 146 ± 28 pA/pF in control and 235 ± 19 pA/pF (p<0.05) in long‐term morphine treated colonic neurons. Nicotine‐induced responses were similar in neurons from α7, α5 and β2 knock out mice suggesting that these isoforms are not the principal nAChR subunits in the mouse enteric neurons. These findings indicate that enhanced nicotinic responses following prolonged morphine exposure are not associated with morphine dependence and may involve alterations in intracellular signaling pathways. Supported by NIH DA024009