Morphine Causes Pain? Who Knew?

While opiates such as morphine are often referred to as a “gold standard” for pain control, they can have serious drawbacks for some patients. These include tolerance, constipation, and something called pain hyperalgesia: the development of pain hypersensitivity over extended morphine use. This morphine-induced hyperalgesia can be as excruciating as the original pain itself. This paradoxical effect of morphine treatment was typically thought to involve the same mechanism as morphine tolerance (Chu et al., 2006).

However, new research from multiple laboratories in Canada, Italy and the U.S.A. has helped to fill in more of the picture of this strange phenomenon and suggests separate mechanisms for morphine tolerance and hyperalgesia. The authors focus on the spinal cord region called the dorsal horn, an important region in the circuitry of pain processing. Pain-sensing neurons in this region are targeted by morphine, which typically inhibits their output to the brain. The current study identified a signaling cascade between microglia and spinal dorsal horn neurons that increases pain transmission by disrupting chloride concentration in dorsal horn neurons, interfering with the usual therapeutic effects of morphine. The chloride concentration is disrupted by downregulation of the KCC2 receptor.

A key finding of this work was that morphine tolerance took two days longer to develop than morphine hyperalgesia, which appeared after 3 days of morphine injections. In addition, signaling through the TrkB-BDNF pathway was required for development of hyperalgesia, but not for development of morphine tolerance. The disparate time courses and pathways of the two processes suggest that separate cellular and molecular mechanisms are at play. This study provides new insight into the action of opiates on the spinal cord in pain and points to potential future therapies that can be added to morphine treatment for better success overall.

What do you think?

Further Reading:

Chu LF, Clark DJ, Angst MS. (2006). Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study. J Pain. Jan;7(1):43-8.

Ferrini F, Trang T, Mattioli TA, Laffray S, Del’guidice T, Lorenzo LE, Castonguay A, Doyon N, Zhang W, Godin AG, Mohr D, Beggs S, Vandal K, Beaulieu JM, Cahill CM, Salter MW, De Koninck Y. (2013). Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(-) homeostasis. Nat Neurosci. Jan 6. doi: 10.1038/nn.3295.